Initial Treatment Research Articles

Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor treatment in children aged 6-11 years with cystic fibrosis in a real-world setting.

Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF. This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV1, LCI2.5, body mass index(BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models. The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy. Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood.

Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial

Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis. ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed. Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group. Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug. Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".

Prognostic significance of oxygen saturation/fraction of inspired oxygen 3 days after initiation of tocilizumab treatment in patients with COVID-19

BackgroundTocilizumab is effective in treating severe coronavirus disease 2019 (COVID-19). However, the specific time point it acts as a valid indicator of treatment efficacy remains unclear. This study aimed to determine the optimal day for assessing the prognostic value of the oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) and ratio of respiratory rate-oxygenation (ROX) index in patients receiving tocilizumab for COVID-19. MethodsAll patients admitted to our hospital from March 2020 to July 2021 who received tocilizumab for COVID-19 were retrospectively identified from hospital charts. Biodata, medical history, and laboratory tests results were obtained from medical records. The prognostic values of the SpO2/FiO2 and ROX index for predicting mortality were assessed. Cox proportional hazard and receiver operating characteristic curve models were utilized. ResultsOf the 84 included patients, 34 died within 7 days after discharge. The patients who recovered had a mean age of 65 years and were younger than those who died. The multivariate analysis indicated that multiple comorbidities, cancer history, CURB-65 score, neutrophil and lymphocyte counts, neutrophil/lymphocyte ratio, and lactate dehydrogenase levels were higher in those who died compared with those who survived. No significant differences were found in dyspnea or total bilirubin levels between the two groups. The SpO2/FiO2 at 3 days post-tocilizumab initiation was strongly associated with survival. ConclusionsThe SpO2/FiO2 on day 3 post-tocilizumab initiation was a predictor of COVID-19 prognosis, which could be employed in determining clinical decisions. Prompt alternative interventions should be considered when this ratio does not improve.

Combined modalities for the rapid diagnosis of patients with suspected tuberculous lymphadenitis: A cross-sectional study.

In settings with high burden of extrapulmonary tuberculosis, the use of various diagnostic modalities can result in superior and quick diagnosis leading to prompt initiation of treatment. This study assessed the diagnostic performance of the fine-needle aspiration cytology (FNAC), Ziehl-Neelsen (ZN) stain, fluorescence microscopy (FM) and cartridge-based nucleic acid amplification test (CBNAAT) in patients with suspected tuberculous lymphadenitis (TBLN). This cross-sectional studyodes, who underwent FNAC. The FNAC samples were subjected to cytomorphological examinati involved 255 patients clinically suspected of TBLN with palpable lymph non, ZN stain, FM and CBNAAT. The diagnostic performance of each modality was compared with CBNAAT, and combined performance was determined. The diagnostic performance of CBNAAT was determined by comparing it with composite reference standard. Of 255 patients, 148 (58.04%) showed features of TBLN on FNAC. The presence of epithelioid cell granulomas with caseous necrosis (67.57%) was the predominant cytomorphological pattern. On ZN stain, FM and CBNAAT, 31 (20.95%), 63 (42.57%) and 100 (67.57%) patients were found to be positive for TBLN, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of CBNAAT was 58.59%, 91.83%, 92% and 58.06%, respectively. Finally, the combination of ZN stain, FM and CBNAAT led to the detection of 88.51% patients with TBLN. Combined use of ZN stain, FM and CBNAAT leads to superior and swift diagnosis of patients with clinically suspected TBLN.

Early Surgery and High Dose Steroids in Treating Patients with Indirect Traumatic Optic Neuropathy: A Meta-Analysis and Systematic Review

Introduction: Optic nerve injury is a devastating cause of permanent visual loss after blunt or penetrating injury occurring in up to 7% of head trauma cases. No single treatment strategy and timing of intervention has proved optimal. Timely and appropriate management is key to improving visual outcomes. We compared whether immediate surgical decompression or steroids would lead to improvement of visual outcomes in individuals with indirect traumatic optic neuropathy. Methods: We searched from several online databases and included studies of patients with direct Optic nerve injury, those who received combined treatment with surgery and steroids, and those with delayed initiation of treatment were excluded. Results: The final search yielded eleven eligible studies. Both interventions showed similar results in improvement of visual function (RR 2.35, 95% CI 0.87 to 6.34, p=0.09, I2 0%). Both early and late intervention also showed similar results in improvement of visual function (RR 1.72, 95% CI 0.89 to 3.35, p=0.11, I2 61%). Among patients who underwent early surgical decompression, the rate of visual acuity improvement was 73% with those who underwent transcranial surgery and 69% with those who underwent endoscopic surgery. Conclusion: This study shows that immediate surgical decompression and early high dose steroid administration are equally effective in improving visual function. Patients with no light perception (NLP) and light perception (LP) pre treatment resulted to better visual improvement with steroids while those with counting fingers (CF) and more than CF pre treatment, resulted to better visual improvement with surgical decompression.

Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection.

Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.

Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists and cancer mortality. A real-world registry

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce cardiovascular events through different mechanisms, nevertheless, their association with cancer remains unclear. Purpose We aim to compare the combined treatment (SGLT2i and GLP1ra) with monotherapy regarding hospitalization or/and death for cancer in a general population and a subgroup of patients with cardiovascular disease (CVD). Methods Retrospective observational study of patients who were prescribed SGLT2i, GLP1ra, or both drugs. Multinomial propensity score was performed in all the population and in a subgroup of patients with CVD (atrial fibrillation [AF], heart failure [HF], coronary artery disease [CAD], peripheral arterial disease [PAD], or cerebrovascular accident [CVA]). The following variables were included to adjust the three groups: Sex, Age, Obesity, diabetes mellitus (DM), high blood pressure (HBP), dyslipidemia (DLP), CAD, HF, AF, and CVA. The three primary outcomes were (i) hospitalization for any cancer, (ii) death for any cancer, and (iii) the combined event in the included population and the subgroup of patients with CVD. The multivariate Cox regression analysis determined the hazard rate (HR) of age, sex, risk factors, and treatment for each outcome. Results We included 14709 patients (11366 with SGLT2i, 1016 with GLP1ra, and 2327 with both treatments) from the treatment initiation. The subgroup with CVD included 4957 (33.7%) patients (Fig 1). After 33 months of median follow-up, the incidence of cancer events was similar between patients with and without CVD (3.4% or 3.7%, respectively). Sex (male) and age were the main risk factors for the 3 outcomes in both groups. Combined treatment and its duration had a protector role for cancer mortality regarding monotherapy with SGLT2i or GLP1ra in all population (HR [95%CI]) 0.2216 [0.106-0.459]; p<0.001 or 0.1928 [0.071-0.519]; p=0.001, respectively) (Fig 2a) and in the subgroup of patients with CVD (HR [95%CI]) 0.279 [0.078-0.994]; p<0.049 or 0.129 [0.024-0.668]; p=0.014, respectively) (Fig 2b), but these results were not found for the outcome of hospitalization for cancer. The combined therapy concerning SGLT2i and duration of treatment showed a protective role against the combined event (HR [95%CI]) 0.709 [0.521-0.967]; p=0.029) and (HR [95%CI]) 0.991 [0.983-0.999]; p=0.032) in the general population but not in the group of CVD. A higher survival rate for any cancer mortality was observed in those patients with the combined therapy respect to monotherapy (SGLT2i or GLP1ra) in the general population (Fig 2c) and the subgroup of patients with CVD (Fig 2d). Conclusions Initiation of combined therapy vs. monotherapy was associated with a lower rate of cancer mortality in the general population and patients with CVD. Future clinical trials and mechanistic studies will clarify the possible role of these drugs on carcinogenesis.Figure 1Figure 2

Virtual patient analysis identifies strategies to improve the performance of predictive biomarkers for PD-1 blockade

Patients with metastatic triple-negative breast cancer (TNBC) show variable responses to PD-1 inhibition. Efficient patient selection by predictive biomarkers would be desirable but is hindered by the limited performance of existing biomarkers. Here, we leveraged in silico patient cohorts generated using a quantitative systems pharmacology model of metastatic TNBC, informed by transcriptomic and clinical data, to explore potential ways to improve patient selection. We evaluated and quantified the performance of 90 biomarker candidates, including various cellular and molecular species, at different cutoffs by a cutoff-based biomarker testing algorithm combined with machine learning-based feature selection. Combinations of pretreatment biomarkers improved the specificity compared to single biomarkers at the cost of reduced sensitivity. On the other hand, early on-treatment biomarkers, such as the relative change in tumor diameter from baseline measured at two weeks after treatment initiation, achieved remarkably higher sensitivity and specificity. Further, blood-based biomarkers had a comparable ability to tumor- or lymph node-based biomarkers in identifying a subset of responders, potentially suggesting a less invasive way for patient selection.

Sustained paradoxical vasodilation and blood pressure lowering in response to sympathetic stimulation as markers of disease severity and poor survival in primary AL amyloidosis.

Abstract Background AL patients present sustained paradoxical vasodilation in response to sympathetic stimulation by cold pressor test (CPT). The clinical relevance of this finding is unknown. Purpose We investigated the association between CPT-induced vascular and hemodynamic responses with clinical characteristics of the disease in AL amyloidosis. Methods We consecutively recruited 113 newly diagnosed patients with AL amyloidosis before treatment initiation. High resolution ultrasonography was used to measure the maximum vasodilation of the brachial artery in response to a cold stimulus and 3 minutes after its withdrawal. Systolic (SBP) and diastolic blood pressure (DBP) were measured at the same timepoints. Clinical and laboratory makers of autonomic dysfunction were also measured in a subgroup of the population. All-cause and cardiovascular (CV) mortality were defined as end-points of the study. Results Sustained vasodilation post CPT (%pCPT) was associated with markers of autonomic dysfunction, namely dipping status (p<0.05) and sudomotor dysfunction (p=0.064) and with NYHA stage, baseline NTproBNP and heart failure (p<0.05 for all). DBP%pCPT was associated with the neuropathy symptom scale (NSS Autonomous, p=0.032), while SBP%pCPT was inversely associated with Mayo stage. Vasodilation%pCPT was independently associated with CV death (adjusted HR=1.154, p=0.017) while both DBP%pCPT (HR=0.955, p=0.027) and SBP%pCPT (HR=0.947, p=0.04) were independently associated with all cause death (adjusted for the core model including age, sex, SBP, Mayo stage and nerve involvement). Overall survival was worse in AL patients who demonstrated a decrease in SBP%pCPT than in those who exhibited an increase or kept it stable (log rank test, p=0.024). The same applies to DBP%pCPT(log rank test, p=0.002). Regarding CV death, Vasodilation%pCPT above 5.86% was associated with increased risk of CV death (log rank test, p=0.002). Conclusions In AL amyloidosis, sustained paradoxical vasodilation and decreased SBP and DBP in response to sympathetic stimulation were associated with autonomic dysfunction, more severe cardiac involvement and poor survival.

Microfibrillar-associated protein 4 as a predictive biomarker of treatment response in patients with chronic inflammatory diseases initiating biologics: secondary analyses based on the prospective BELIEVE cohort study.

Currently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs). To determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs. The BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn's disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14-16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14-16 weeks. 211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group. A high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors.

Beyond LDL-cholesterol: effects of alirocumab on the human apolipoproteome

Abstract Introduction The PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) trial enrolled 300 participants with longitudinal plasma samples available at four time points (enrollment, 24 hours, 4 weeks, 52 weeks), of which 266 completed the 52-week follow-up. Purpose Expanding on a previous investigation employing apolipoprotein proteomics in patients with coronary heart disease, the current study aimed to evaluate the impact of the monoclonal antibody alirocumab on apolipoprotein and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. Methods A mass spectrometry assay was employed to quantify 15 apolipoproteins. Linear mixed-effects models assessed the impact of timepoints and treatments (alirocumab: n = 131, placebo: n = 135, in addition to statins) on apolipoprotein levels. Results Alirocumab led to a fast rise in PCSK9 levels, with a marked increase [inter-quartile range] of 262% [207%] as early as 24 hours after treatment initiation, followed by more pronounced elevations at 4 weeks and 52 weeks, reaching 1575% [813%] and 1480% [747%], respectively (P < 0.001 for all comparisons). At 52 weeks, the ApoB reduction compared with enrollment was -75% [10%] with alirocumab vs. -43% [19%] with placebo (P < 0.001, between groups), while the change in LDL-C was -88% [9%] with alirocumab vs. -54% [19%] with placebo (P < 0.001). Alongside significantly greater reductions in ApoC2 (P = 0.0041) and ApoC3 (P < 0.001) with alirocumab, ApoE changed by -41.6% [21.1%] with alirocumab compared to -15.4% [24.5%] with placebo (P < 0.001). Overall, there was no impact on Apo(a) levels compared to baseline. Conclusion The rapid increase in PCSK9 levels after 24 hours suggests immediate immunocomplex formation. A compensatory rise in PCSK9 production may contribute to later elevations. Alirocumab not only lowered LDL-C but also achieved a sustained reduction in very low-density lipoprotein-associated apolipoproteins (ApoC2, ApoC3, and ApoE), indicating additional benefits of PCSK9 inhibitors.

High discontinuation rate of statins among PCSK9i users: a nationwide study from 2015-2023

Abstract Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are recommended as additional lipid-lowering drug treatment for high-risk patients if the low-density lipoprotein cholesterol (LDL-C) targets are not achieved with statins and ezetimibe alone. Nationwide data from clinical practice on the use of PCSK9i are lacking. In 2015, PCSK9i became available in Norway with reimbursement restricted to patients with familial hypercholesterolemia (FH) and/or atherosclerotic cardiovascular disease (ASCVD) with LDL-C above certain levels. Purpose To investigate the use and adherence of lipid lowering drugs among a nationwide cohort of PCSK9i users, utlizing complete pharmacy dispensation data. Methods Information on all PCSK9i users ≤80 years with at least one year of follow-up after the first dispensation were extracted from the Norwegian Prescribed Drug Registry. We evaluated adherence to PCSK9i by calculating the proportion of days covered (PDC) during the initial year of PCSK9i therapy. Poor adherence was defined as PDC <80%, and discontinuation was defined as a gap in treatment ≥180 days during the follow-up period. We analyzed treatment patterns of statins and ezetimibe during the 1-year period before and after PCSK9i initiation by determining the proportion of patients with at least one dispensation of statin and/or ezetimibe treatment. Results A total of 2,997 PCSK9i users were identified. Median age at treatment initiation was 62 (IQR: 13) years and 43% were female. Non-adherence to PCSK9i was observed in 16% of the patients, and 18% discontinued treatment (Table). Non-adherence to PCSK9i was more prevalent in females, and in the lowest and highest age quartiles. No significant difference in non-adherence was found among patients with ASCVD compared to patients with FH. In the year preceding PCSK9i initiation, 74% of patients used statins (including combinations with ezetimibe), 11% used ezetimibe monotherapy, and 15% did not use any statin or ezetimibe treatment (Figure). During the year following PCSK9i initiation, 35% used statins (including combinations), 17% used ezetimibe monotherapy, and 48% did not use any statin or ezetimibe treatment. Among patients with ASCVD, 72% used statins prior to PCSK9i initiation, and 22% used statins after. Among patients with FH, 77% used statins prior to PCSK9i initiation, while 51% used statins after. Conclusion In this nationwide study of incident PCSK9i users, we observed a substantial decrease in usage of statins and ezetimibe following PCSK9i initiation. Further, almost 1 in 5 patients discontinued treatment with PCSK9i. There is a large potential for optimizing treatment and adherence to PCSK9i and conventional lipid-lowering drugs among Norwegian patients with ASCVD and familial hypercholesterolemia.Adherence and discontinuation to PCSK9iUse of statin and ezetimibe

Association between surgery treatment delays and survival outcomes in patients with esophageal cancer in Hebei, China

IntroductionThe delays in cancer therapies have the potential to impact disease progression by allowing the unchecked growth and spread of cancer cells. However, the understanding of the association between treatment waiting time and survival outcomes in patients with esophageal cancer (EC) is limited. This study aims to assess the impact of waiting time on survival outcomes among EC patients in Hebei province, which is recognized as one of the high-risk areas for EC in China.MethodsA total of 9,977 non-metastatic EC patients who underwent surgical treatment were identified between 2000 and 2020. The survival outcomes of overall survival (OS) and cancer-specific survival (CSS) were determined using the Kaplan-Meier methodology. Univariate and multivariate Cox regression analysis was employed to evaluate the impact of treatment delays on OS and CSS.ResultsThe average delay time for initiating EC surgical treatment after diagnosis was 1.31 months (95%CI=1.29–1.34). Patients with a long delay (≥ 3 months) in treatment, comprising 9977 EC patients, exhibited significantly lower rates of 3-, 5-, and 10-year OS and CSS compared to those without any delay in treatment initiation. A long delay in EC treatment independently associated with an elevated risk of all-cause and cancer-cause mortality among various patient subgroups, including males, older individuals, single individuals, low-income patients, residents of nonmetropolitan counties, as well as those diagnosed with poorly differentiated and stage IV EC.DiscussionThe long delay of treatment initiation impacts the outcomes of OS and CSS in EC patients. Optimizing treatment timing may enhance life expectancy for individuals diagnosed with EC.

Can the presence of aortic or coronary artery calcifications in the standard of care baseline CT or PET-CT scan of patients with Hodgkin or non-Hodgkin lymphoma be used as a predictor of MACE?

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR <60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

A novel murine wire injury based infectious endocarditis model aggravates aortic valve stenosis

Abstract Background With mortality rates up to 40% under optimal medical treatment, infectious endocarditis (IE) remains one of the deadliest infectious diseases worldwide. In the early stages of IE, diagnosis and treatment initiation are often difficult and research is limited due to unreliable models. Most murine IE models rely on permanent prosthetic wire placement and i.v. bacterial injection, thus making it inadequate to study IE pathophysiology with the aim to reflect the course of disease in humans. Purpose To develop a reproducible murine IE model, based on aortic valve injury preceding intravenous S. aureus bacterial challenge. Methods Using a wire-injury model we induced endothelial lesions. 72h after wire injury (WI), we performed intravenous bacterial challenge using S. aureus. Echocardiography was performed to confirm bacterial vegetations and assess valvular function. Cross sections of valvular leaflets were prepared for scanning electron microscopy (SEM). Macrophage, neutrophil and S. aureus-specific immunofluorescence staining was performed and visualized by immunofluorescence microscopy. Bacterial cultivation was performed from peripheral blood and valve tissue. Systemic immune response was analyzed using flow cytometry. Results WI induced endothelial damage in all mice verified using scanning electron microscopy imaging. The combination of wire injury and injection of 10^5 and 10^6 colonies-forming-units (CFU) S. aureus reliably caused IE validated via in vivo echocardiography as well as S.aureus immunofluorescence staining and SEM imaging. Mice undergoing bacterial challenge responded with significant neutrophilia in the blood. Using 10^6 CFU S. aureus was associated with an increased mortality, liver and kidney abscess formation due to systemic bacterial spreading compared to 10^5 CFU. Peak velocity across the aortic valve and aortic valve leaflet thickness as markers for aortic valve stenosis were increased in IE compared to WI only mice. Aortic regurgitation was more prevalent after bacterial challenge mediating increased left ventricular volumes, meanwhile ejection fraction was not altered. Immunofluorescence staining revealed a pro-inflammatory milieu including increased macrophage and neutrophil infiltration in IE compared to WI only mice. Conclusion In vivo echocardiography and ex vivo histological staining revealed reliable IE induction using our new model with S. aureus concentrations of 10^5 CFU. The additional bacterial challenge causes a more severe aortic valve stenosis compared to WI only mice, potentially due to an observed increase in valvular inflammation.Fig 1 Scanning electron microscopy after

VExUS score improvement is associated with better outcomes in acute decompensated heart failure

Abstract Background Venous Excess Ultrasound Score (VExUS) has recently emerged as a non-invasive tool for venous congestion assessment in acute decompensated heart failure (ADHF). Although VExUS is associated with cardiorenal syndrome, the prognostic role regarding hard outcomes in ADHF is still unknown. Purpose To evaluate whether dynamic changes in VExUS within 72 hours after Cardiovascular Intensive Care Unit (CICU) admission is associated with in-hospital mortality in ADHF patients. Methods Prospective cohort study enrolling consecutive patients with ADHF admitted to CICU of a tertiary public hospital. VExUS evaluations ranging from 0 (no congestion) and 3 (severe congestion) and assessing the inferior vena cava, hepatic, and portal veins flow, were initially performed within 24 hours of admission and re-evaluated at 72 hours (third day) after treatment initiation. Changes in VExUS scores were compared between these two time points. Mann-Whitney test and logistic regression was performed to evaluate VExUS improvement association with mortality. Results Between October 2022 and January 2024, 81 patients were admitted to the CICU due to ADHF. Following the exclusion of 10 patients who were not assessed within the first 24 hours, 71 patients were included in the final analysis. Mean age was 65 ± 13.3 years, with 66.7% being male. Ischemic etiology was identified in 40.7%, and atrial fibrillation was present in 34.6%. Mean left ventricular ejection fraction was 27.4% ± 12.2, and 64.2% had right ventricular dysfunction. Upon admission, 73.2% were classified as B and 23.9% as C hemodynamic profiles. Overall in-hospital mortality was 25.9%. In-hospital mortality across VExUS categories assessed in the third day was 16.7%, 12.5%, 28.6% e 40%, for VExUS 0-3, respectively. The median VExUS variation between the two time points was greater in patients who survived [-1 vs. 0; p=0.030] and VExUS improvement at 72 hours was associated with a 46% decrease in hospital mortality for each class reduction (OR=0.536; 95% CI 0.29-0-81; p=0.043 - Figure 1). Conclusion Improvement in VExUS score between admission and 72 hours is associated with reduced in-hospital mortality. This finding highlights the potential role of dynamic VExUS monitoring for identifying delayed treatment response patients. Thus, changes in VExUS emerged as a prognostic tool offering a pathway to potentially intensify treatment strategies for high-risk patients with ADHF.VExUS score changes within 72 hours

Parallel improvement of arterial stiffness with weight loss following intensification of antidiabetic treatment

Abstract Background Arterial stiffness is a marker that can flag increased cardiovascular disease risk in patients with type 2 Diabetes Mellitus (T2DM), while weight management plays a crucial role for the management of glycemic control and prevention of complications in these patients. Purpose To investigate the effects of novel antidiabetic agents on arterial stiffness in T2DM patients as well as potential associations with their weight status before and after treatment. Patients and Methods We enrolled 118 consecutive patients under stable antidiabetic therapy. According to their physician they start treatment with an additional antidiabetic agent; either dipeptidyl peptidase-4 inhibitor (DPP-4i, n=19), or glucagon like peptide-1 receptor agonist (GLP-1RA, n=50) or sodium/glucose cotransporter-2 inhibitor (SGLT-2i, n=49). Body Mass Index (BMI) along with carotid-femoral pulse wave velocity (PWV) as a biomarker of arterial stiffness were measured at baseline and 3 months after treatment intensification. Results There were no differences between the study groups regarding their sex, age and other traditional risk factors or the values of PWV and BMI at baselined (p=NS for all). All groups achieved better glycemic control in terms of HbA1c values between baseline and follow-up; from 7.4±1.2% to 7.4±1.2% in the DPP4i group (p<0.001 for all), from 8.6±0.7% to 6.7±0.8% in the GLP-1RA group (p=0.07) and from 7.7±1.1% to 6.7±0.7% in the SGLT-2i group (p<0.001). PWV showed a decrease from 10.6±2.7 to 9.0±1.6 m/sec (p=0.001) in the DPP4-i group, from 11.2±2.5 to 9.3±2.2 m/sec (p<0.001) in the GLP-1RA group and from 10.7±2.4 to 8.9±2.0 m/sec (p=0.001) in the SGLT-2i group as presented in Figure 1. Regarding BMI, a reduction in the values between groups from baseline to follow-up was also observed; from 27.4±5.3 to 26.1±5.0 kg/m2 for the DPP-4i group, from 33.6±4.9 to 31.5±4.6 kg/m2 for the GLP-1RA group, from 31.8±5.5 to 30.5±5.6 kg/m2 for the SGLT-2i group (p<0.001 for all). Moreover, in the entire study population there was significant correlation between PWV and BMI improvement following treatment initiation (rho=0.247, p=0.007) (Figure 2). Conclusion Diabetes mellitus treatment intensification with GLP1-RA or SGLT-2i or DPP4i, ameliorated arteriosclerosis, improved PWV and BMI while there is significant association between BMI and PWV improvement.Changes in PWV values among the groupsCorrelation between deltaBMI & deltaPWV

Cardiological monitoring during BTK inhibitor, ICI, and RAF/MEK inhibitor therapy: the single-center prospective registry for cardiovascular events under new cancer therapies (RECENT)

Abstract Background The advent of novel targeted cancer therapies have revolutionized cancer treatment. However, concerns about their impact on cardiovascular health persist and current guidelines recommend cardiac monitoring. Yet, prospective data on incidence rates of cardiovascular events are lacking. The Registry for Cardiovascular Events under new cancer Therapies (RECENT) aims to systematically assess clinical as well as subclinical cardiovascular incidents in patients undergoing these novel therapies to identify baseline risk factors and derive individualized monitoring strategies. Methods This ongoing single-center prospective registry enrolls cancer patients receiving BTK inhibitors, ICI, or RAF/MEK inhibitors. Baseline cardiovascular assessment, risk stratification according to HFA-ICOS risk score, and follow up visits for 12 months at three-monthly intervals (including ECG, biomarkers and echocardiography) during treatment are conducted. Treatment-related events, in particular hypertension, arrhythmias, cancer therapy-related cardiac dysfunction (CTRCD), and (peri-) myocarditis, as defined according to current guideline recommendations, are recorded. Results We report data of the first 85 patients (60.9 ± 14.7 years, 52.9% male) included in this ongoing registry. Of those, 17/85 patients received treatment with BTK inhibitors (20%), 45/85 with ICI (53%) and 23/85 with RAF/MEK inhibitors (27%). Most common treatment indication were dermatological (39/85, 45.9%), hematologic (17/85, 20%), urological (13/85, 15.3%) and head and neck (11/85, 12.9%) cancers. Before treatment, the majority of patients were stratified as low-risk (31/85) or moderate-risk (32/85), and 22/85 (25.9%) as high-risk. 7/85 (8.2%) patients were newly diagnosed with cardiovascular disease at baseline visit, resulting in a change in risk category and subsequent initiation of cardiovascular treatment. This includes 3 patients who had been initially categorized as low-risk and would not have been referred for further cardiac workup due to current guideline recommendations. The six months follow up visit has been completed in 44/85 patients. Among these, 1/20 patients (5%) with ICI developed a perimyocarditis and 2/11 patients (18.2%) with BTK inhibitors developed atrial fibrillation. 1/13 patients (7.7%) with RAF/MEK inhibitor therapy, classified as low-risk at baseline, developed asymptomatic CTRCD, which resolved after initiation of cardioprotective drug therapy. Conclusion This interim analysis of the RECENT registry indicates benefit of a structured baseline cardiac assessment prior to cancer treatment in all patients, irrespective of the initial risk stratification. Contrary to current guidelines, which recommend routine echocardiographic monitoring in patients receiving RAF/MEK inhibitors only in high-risk patients, the current data advocate for extending this also to low-risk patients to detect subclinical deterioration of the cardiovascular status.

Correlation between a 2-week change in platelet count and clinical outcomes after the initiation of ravulizumab treatment in adult patients with atypical hemolytic uremic syndrome: post-hoc analysis of the phase III trial

Correlation between a 2-week change in platelet count and clinical outcomes after the initiation of ravulizumab treatment in adult patients with atypical hemolytic uremic syndrome: post-hoc analysis of the phase III trial

Impact of SLGT2 inhibitors treatment initiation on the reduction of atrial and ventricular arrhythmias in patients with implanted cardiac defibrillator

Abstract Introduction Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have been associated with improved prognosis in patients with heart failure; however, their impact on atrial arrhythmic (AA) and ventricular arrhythmic (VA) events is not fully understood. Methods Retrospective multicentric study of heart failure patients with implantable cardiac defibrillator device (ICD) from 2015 to 2020 with or without cardiac resynchronization therapy (CRT) receiving SGLT2 inhibitors. Device-registered arrhythmic events were analyzed and compared in two time periods for each patient: one year before and one year after starting SGLT2i. Relevant VA were defined as the occurrence of any sustained VT (SVT) (>30 seconds), ventricular fibrillation (VF), or appropriate therapy (antitachycardia pacing or shock). All VA included all the relevant VA and the occurrence of non-sustained ventricular tachycardia (NSVT). AA included atrial fibrillation (AF) burden, and episodes of more than 24 hour of AF. Results A total of 195 patients (66.8 [61.3-73.1] years, 18.5% women) were included. A reduction was observed in the percentage of patients with any VA (pre: 52.3% vs post: 30.3%; P < 0.001) and clinically relevant VA (excluding NSVT) (pre: 21.5% vs post 8.7%; P < 0.001) in the post-SGLT2i period. There was also a reduction in the number of episodes per patient/year of NSVT (pre: 2 (1-5) vs post: 1 (0-2); P < .001), and SVT (pre: 1 (1-3) vs post: 0 (0-2); p = 0.046). This protective effect was also observed after controlling confusion factors (Any VA: OR 0.35 (0,24-0,50); p<0.001 and relevant VA: OR 0.30 (0,17-0,52); p<0.001). However, no differences were observed in the prevalence of AA (24.7% vs 18.8%; P = 0.117) or the burden of atrial fibrillation (pre: 0% (0-0.1) vs post 0% (0-0); p = 0.097). Conclusions Following the initiation of SGLT2i treatment, a reduction in the percentage of patients with relevant VA was observed. However, this effect was not observed for AA.Figure 1Figure 2