High Risk Of Disease Progression Research Articles

Clinicopathological and molecular genetic features of neuromuscular choristoma-associated desmoid type fibromatosis

Objective: To investigate the clinicopathological and genetic characteristics of neuromuscular choristoma-associated desmoid type fibromatosis (NMC-DF). Methods: The clinical morphological and immunohistochemical features of 7 NMC-DF cases diagnosed from January 2013 to January 2023 in Beijing Jishuitan Hospital were retrospectively analyzed. A series of neuromuscular choristoma and neuromuscular choristoma-associated desmoid type fibromatosis were evaluated for CTNNB1 mutations, and hotspot mutations for CTNNB1 were tested in 4 NMC-DF cases using Sanger sequencing. Results: The tumors were collected from 3 females and 4 males, aged 1 to 22 years (mean 7.1 years), involving the sciatic nerve (n=4), brachial plexus (n=2) or multiple nerves (n=1). The course of the disease spanned from 3 months to 10 years. Two cases were recurrent tumors. All the 7 NMC cases showed endoneurial intercalation of mature skeletal muscle fibers among the peripheral nerve fascicles, and the histologic features of the NMC-DF were strikingly similar to the conventional desmoid-type fibromatosis. By immunohistochemistry, all NMC and NMC-DF cases showed aberrant nuclear staining of β-catenin (7/7), the muscle cells in NMC were intensely immunoreactive for desmin, and the admixed nerve fibers were highlighted by NF and S-100 (7/7). Four NMC and NMC-DF had CTNNB1 mutations, 3 c.121A>G (p.T41A) and 1 c.134C>T (p.S45F). Follow-up of the 7 cases, ranging from 22 to 78 months, showed tumor recurrence in 2 patients at 3 and 8 months respectively after the first surgical resection, of which 1 patient underwent above-knee amputation. No recurrence occurred in other cases with tumor excision and neurological reconstruction surgery. There was no metastasis occurred in the 7 cases. Conclusions: NMC is a rare congenital lesion with differentiated mature skeletal muscle tissue found in peripheral nerve fascicles, and approximately 80% of patients with NMC develop a soft tissue fibromatosis. CTNNB1 mutation in the Wnt signaling pathway may be involved in the pathogenesis of NMC and NMC-DF, and S45F mutations seems to have a higher risk of disease progression.

Value of Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) in Assessing Liver Fibrosis in Metabolic Dysfunction-Associated Liver Disease: A Comprehensive Review of its Serum Biomarker Role.

Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is a broad condition characterized by lipid accumulation in the liver tissue, which can progress to fibrosis and cirrhosis if left untreated. Traditionally, liver biopsy is the gold standard for evaluating fibrosis. However, non-invasive biomarkers of liver fibrosis are developed to assess the fibrosis without the risk of biopsy complications. Novel serum biomarkers have emerged as a promising tool for non-invasive assessment of liver fibrosis in MAFLD patients. Several studies have shown that elevated levels of Mac-2 binding protein glycosylation isomer (M2BPGi) are associated with increased liver fibrosis severity in MAFLD patients. This suggests that M2BPGi could serve as a reliable marker for identifying individuals at higher risk of disease progression. Furthermore, the use of M2BPGi offers a non-invasive alternative to liver biopsy, which is invasive and prone to sampling errors. Overall, the usage of M2BPGi in assessing liver fibrosis in MAFLD holds great promise for improving risk stratification and monitoring disease progression in affected individuals. Further research is needed to validate its utility in clinical practice and establish standardized protocols for its implementation.

Muscle MRI as a biomarker of disease activity and progression in myotonic dystrophy type 1: a longitudinal study

IntroductionMyotonic dystrophy type 1 (DM1) is an autosomal dominant disease characterized by myotonia and progressive muscular weakness and atrophy. The aim of this study was to investigate the usefulness of longitudinal muscle MRI in detecting disease activity and progression in DM1, and to better characterize muscle edema, fat replacement and atrophy overtime.Materials and methodsThis is a prospective, observational, longitudinal study including 25 DM1 patients that performed at least two muscle MRIs. Demographic and genetic characteristics were recorded. Muscular Impairment Rating Scale (MIRS) and MRC score were performed within 3 months from MRIs at baseline (BL) and at follow-up (FU). We analysed 32 muscles of lower body (LB) and 17 muscles of upper body (UB) by T1 and STIR sequences. T1-, STIR- and atrophy scores and their variations were evaluated. Correlations between MRIs’ scores and demographic, clinical and genetic characteristics were analysed.ResultsEighty (80%) of patients showed fat replacement progression at FU. The median T1 score progression (ΔT1-score) was 1.3% per year in LB and 0.5% per year in UB. The rate of fat replacement progression was not homogenous, stratifying patients from non-progressors to fast progressors (> 3% ΔT1-score per year). Half of the STIR-positive muscles at BL showed T1-score progression at FU. Two patients with normal MRI at baseline only showed STIR-positive muscle at FU, marking the disease activity onset. STIR positivity at baseline correlated with fat replacement progression (ΔT1-score; p < 0.0001) and clinical worsening at FU (ΔMRC-score; p < 0.0001). Sixty-five (65%) of patients showed STIR- and fat replacement-independent muscle atrophy progression, more evident in UB.ConclusionsMuscle MRI represents a sensitive biomarker of disease activity, severity, and progression in DM1. STIR alterations precede fat replacement and identify patients with a higher risk of disease progression, while T1-sequences reveal atrophy and fat replacement progression before clinical worsening.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals or no treatment in England: a retrospective cohort study

Objective To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. Methods Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18–64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. Results Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3–1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). Conclusion Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.

MicroRNA and renal fibrosis in autosomal dominant polycystic kidney disease: a longitudinal study.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder that may progress to kidney failure, accounting for 5-10% of all patients with end-stage kidney disease (ESKD). Clinical data, as well as molecular genetics and advanced imaging techniques have provided surrogate prognostic biomarkers to predict rapid decline in kidney function, nonetheless enhanced tools for assessing prognosis for ADPKD are stillneeded. The aim of this study was to analyze specific microRNAs involved in the pathogenesis of ADPKD and in the development of renal fibrosis, evaluating their potential role as predictors of renal function loss. We evaluated kidney function by estimated glomerular filtration rate (eGFR) in 32 ADPKD patients in different stages of kidney disease at T0 and after a 24-month follow up (T1). Patients were divided into two groups: Rapid disease progression ([RP], n 15) and Non-rapid disease progression ([NRP], n 17), according to the Mayo Clinic classification criteria. At T0, ADPKD patients underwent plasma sampling for quantitative analysis of h-miR-17-5p, h-miR-21-5p and h-miR-199a-5p microRNA expression, using the quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) method and a 3T magnetic resonance imaging (MRI), using an advanced MRI imaging protocol, for the quantification of total kidney volume (TKV), total perfusion volume (TPV) and total fibrotic volume (TFV). The expression of h-miR17-5p was higher (p < 0.05) in ADPKD patients with rapid disease progression. h-miR-17-5p, h-miR-21-5p and h-mir-199-5p showed a positive and significant correlation with the eGFR slope (mL/min/1.73 m2/year) (p < 0.05) but not with the eGFR at both T0 and T1. Both total fibrotic volume (cm3) and height-adjusted total fibrotic volume (cm3/m) were positively and significantly correlated to h-miR 21-5p and h-miR 199-5p (p < 0.05), but not to total kidney volume (cm3) and height-adjusted total kidney volume (cm3/m). The microRNAs we studied were associated with fibrosis and renal damage, suggesting their possible role as biomarkers able to identify ADPKD patients at high risk of disease progression regardless of the degree of kidney function, and therefore suitable for medical therapy, and may help uncovering new molecular mechanisms underlying cystogenesis.

Characteristics and outcomes of patients with COVID-19 at high risk of disease progression receiving sotrovimab, oral antivirals, or no treatment: a retrospective cohort study

BackgroundThe clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe characteristics and clinical outcomes of highest risk patients with COVID-19 receiving early COVID-19 treatments in Scotland.MethodsRetrospective cohort study of non-hospitalized patients diagnosed with COVID-19 from December 1, 2021–October 25, 2022, using Scottish administrative health data. We included adult patients who met ≥ 1 of the National Health Service highest risk criteria for early COVID-19 treatment and received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of COVID-19 diagnosis or early COVID-19 treatment. Baseline characteristics and acute clinical outcomes in the 28 days following index were reported. Values of ≤ 5 were suppressed.ResultsIn total, 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709: eligible highest risk untreated). Patients aged ≥ 75 years accounted for 6.9% (n = 34/492), 21.0% (n = 58/276), 16.9% (n = 12/71) and 13.2% (n = 225/1709) of the cohorts, respectively. Advanced renal disease was reported in 6.7% (n = 33/492) of sotrovimab-treated and 4.7% (n = 81/1709) of untreated patients, and ≤ 5 nirmatrelvir/ritonavir-treated and molnupiravir-treated patients. All-cause hospitalizations were experienced by 5.3% (n = 25/476) of sotrovimab-treated patients, 6.9% (n = 12/175) of nirmatrelvir/ritonavir-treated patients, ≤ 5 (suppressed number) molnupiravir-treated patients and 13.3% (n = 216/1622) of untreated patients. There were no deaths in the treated cohorts; mortality was 4.3% (n = 70/1622) among untreated patients.ConclusionsSotrovimab was often used by patients who were aged < 75 years. Among patients receiving early COVID-19 treatment, proportions of 28-day all-cause hospitalization and death were low.

Social Factors Associated with the Risk of Glaucoma Suspect Conversion to Glaucoma: Analysis of the Nationwide All of Us Program

To examine social factors associated with the 5-year risk of glaucoma suspects (GS) converting to open-angle glaucoma (OAG). Retrospective cohort analysis. We screened for participants diagnosed with GS in the All of Us database. Cases that converted to OAG within 5 years of GS diagnosis (the "conversion group") were compared with control cases that did not convert. Demographic, socioeconomic and health-care utilization data of the cases were extracted and compared between the conversion group and the control group. Multivariable Cox proportional hazards modeling was used to identify potential factors associated with the risk of conversion. Hazard ratios (HRs) of significant factors associated with the risk of conversion. A total of 5274 GS participants were identified, and 786 (15%) cases converted to OAG within 5-year follow-up. The 2 groups showed significant differences in age, race, gender, employment status, income/education level, history of intraocular surgery, and health-care utilization patterns. In the multivariable model, African American/Black race (HR :1.70 [95% confidence interval (CI) 1.44-2.00]), older age at GS diagnosis (1.17 [95% CI 1.09-1.25]), male gender (1.30 [95% CI 1.13-1.50], no history of recreational drug use (1.23 [1.07-1.42]), history of intraocular surgery (1.60 [95% CI 1.02-1.53]), and having more reasons for delayed health-care access (2.27 [95% CI 1.23-4.18]) were associated with a greater hazard of conversion, while being employed (0.71 [95% CI 0.60-0.86]) was associated with a smaller hazard of conversion (P<0.05 for all). Several social factors were associated with the conversion from GS to OAG, which may help to identify patients at higher risk of disease progression. Future studies are needed to examine the basis for these findings and the potential interventions that could address them. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Prognostic Value of Proliferative Activity in Cutaneous Melanoma: A Pilot Study Evaluating the Mitotic Rate and Ki67 Index to Predict Patient Outcomes.

Proliferative activity in cutaneous melanomas can be appreciated both histopathologically by counting mitotic figures and immunohistochemically through the Ki67 index, but the prognostic value of each method is still a matter of debate. In this context, we performed a retrospective study on 33 patients diagnosed with cutaneous melanomas between 2013 and 2018 in order to evaluate progression-free survival and overall survival. Multivariate Cox proportional hazards regression was performed by considering both clinical histopathological and immunohistochemical features. The mitotic rate was significantly independently associated with both outcomes, while the Ki67 index was not an independent prognostic factor. However, the Ki67 predictive accuracy could be improved by establishing both a cut-off value and a standardized protocol for evaluating its expression. Until these desiderata are met, the mitotic rate remains superior to the Ki67 index for predicting prognosis in cutaneous melanomas, as also has the advantage of being easily interpreted in a standard histopathological examination regardless of the pathologist's experience and with no further financial expenses. Importantly, this is one of very few articles that has shown perineural invasion to be an independent prognostic factor for both progression-free survival and overall survival in cutaneous melanomas. As a consequence, this parameter should become a mandatory feature in the histopathological evaluation of cutaneous melanomas as it can improve the identification of patients who are at high risk for disease progression.

Role of dynamic ctDNA monitoring in cervical and anal epidermoid carcinomas under curative chemoradiation.

3141 Background: Cervical and anal canal squamous cell carcinoma (SSC) are a significant health problem in underdevelopment countries. Definitive chemoradiation (CRT) is the standard-of-care (SOC) approach for curative treatment in locally advanced disease. Due to the common substantial local inflammation during CRT, the conventional clinical image cannot identify non-responders early. In this scenario, the evaluation of circulating tumor DNA (ctDNA) is a promising tool for real-time tumor response monitoring. Methods: We performed a prospective multicentric cohort study of patients treated between 2020 and 2023 in tertiary oncologic centers in Brazil to evaluate the role of ctDNA dynamic monitoring in epidermoid cervical (CC) and anal cancer (AC) T1-4, N0-1, M0 by AJCC 8th edition and candidates to complete curative CRT. The cDNA was assessed by Signatera test at D1, D29, immediately post-treatment, 8 weeks (w) post-CRT, 24w post-CRT, every 6 months (m) in the first 1-2 years(y), and yearly at 3-5y of follow-up (FUP). The primary endpoint was to estimate the correlation of ctDNA with a tumoral response assessed by conventional routine image and clinical evaluation at 8w. Secondary endpoints included a correlation between ctDNA results at different time points with progression-free survival (PFS) and overall survival (OS). The predictive potential of the biomarker was evaluated using receiving operating characteristic (ROC) curve analysis. Results: We included 33 patients, and 27 were evaluable with ctDNA, with a median FUP of 10m. The majority were female (n=23, 85.1%), and 3 (11%) were HIV-positive(+). Most patients presented with positive nodes and stage III disease (n=18, 66.6%). In the AC group (n=15), the majority received CRT with capecitabine and cisplatin (n=12, 55.5%); in the CC group (n=12), all pts received cisplatin. All pts tested expressed ctDNA+ before treatment. At 8w, images had a sensitivity of 42.8% and specificity of 100% for disease progression (area under the curve [AUC] 0.714), while ctDNA yielded a sensitivity of 85.7% and specificity of 89.4% (AUC 0.875). The ctDNA+ immediately after CRT ended (32%) was consistent with ctDNA+ at 8w (30.7%) and 24w (30%). Pts with ctDNA+ immediately post CRT have a higher risk of disease progression with PFS of 8.2m in ctDNA+ and not reached in ctDNA- group (HR:17.5; IC95%:1.9-157.3; p=0.01). Data are immature for OS analysis. Conclusions: CtDNA immediately post-CRT has a high predictive value in patients with anal and cervical tumors in early access CRT non-responders, who are at a high risk of disease progression. This biomarker should be considered for tailoring strategies of treatment escalation in this population.

Associations of Urine and Plasma Metabolites With Kidney Failure and Death in a Chronic Kidney Disease Cohort

Rationale & ObjectiveBiomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. Study DesignProspective metabolome-wide association study. Setting & ParticipantsPersons with CKD enrolled in the German CKD Study (GCKD) with metabolite measurements; with external validation within the Atherosclerosis Risk in Communities Study. Exposures1,513 urine and 1,416 plasma metabolites (Metabolon, Inc.) measured at study entry using untargeted mass spectrometry. OutcomesMain endpoints were kidney failure (KF), and a composite endpoint of KF, eGFR <15 mL/min/1.73m2, or 40% decline in eGFR (CKE). Death from any cause was a secondary endpoint. After a median of 6.5 years follow-up, 500 persons experienced KF, 1,083 experienced CKE and 680 died. Analytical ApproachTime-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design, with external validation. Results5,088 GCKD participants were included in analyses of urine metabolites and 5,144 in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (hazard ratio: 1.95, 95% confidence interval: 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, CKE, and death. External validation of the identified associations of metabolites with KF or CKE revealed direction-consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LimitationsUse of observational data and semi-quantitative metabolite measurements at a single time point. ConclusionsThe observed associations between metabolites and KF, CKE or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts.

#2632 Quality of life and fatigue burden in individuals living with Complement 3 Glomerulopathy – a real-world study

Abstract Background and Aims C3 glomerulopathy (C3G) has an estimated incidence of 1 to 2 per million per year and is associated with a high risk of disease progression, with approximately 50% of patients reaching kidney failure within ten years of diagnosis; despite this, there are currently limited treatment options available. The impact of C3G on patient fatigue and quality of life (QoL) is well understood but not well described in large scale real-world settings; this study aims to address this. Method Data were drawn from the Adelphi C3G Disease Specific Programme™, a cross-sectional survey with retrospective data collection of C3G-treating nephrologists in France, Germany, Italy, Spain, the United Kingdom (EU5), China, Japan, and the United States (US) from August 2022 – April 2023. Nephrologists completed surveys for 1–9 consecutively consulted C3G patients, reporting patient demographics, treatment history, symptoms and QoL. Patients for whom nephrologists completed a form were then invited to complete a voluntary follow-up questionnaire to capture impact of C3G across QoL metrics including the 5-level EQ-5D version [EQ-5D-5L] (which captures QoL at the time of survey) and the Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue (which captures typical impact of fatigue across the 7 days prior to survey completion). Analyses were descriptive. Results Overall, 111 nephrologists reported on 385 patients (EU5 n=189, China n=60, Japan n=36, US n=100). At the time of the survey, median (interquartile range; IQR) patient age was 42.0 (30.0, 55.0) years and 59% of patients were male. Median (IQR) proteinuria was 1.4 g/24 hr (0.8 g/24 hr-3.0 g/24 hr) and eGFR was 50.0 mL/min/1.73m2 (32.00 mL/min/1.73m2 -70.00 mL/min/1.73m2). Of the 385 patients with physician reported data, 118 patients completed their own matched questionnaire, the majority of which were based in China (EU5 n=33, China n=60, Japan n=6, US n=19). Among these patients who completed the EQ-5D 74% experienced anxiety and/or depression, 65% felt pain and/or discomfort and 63% experienced problems doing their usual activities. QoL was also impacted across the further 2 domains: 42% experienced mobility problems and 30% experienced self-care problems (washing or dressing themself). Fatigue as measured by the FACIT fatigue was commonly reported across all patients; 93% of patients felt tired, 91% felt fatigued, 84% felt listless and 82% felt weak all over. The majority (77%) also reported that they needed to sleep during the day. Fatigue impacted all aspects of the patients’ lives; 47% reported feeling too tired to eat, 62% required some help to conduct their usual activities, 71% struggled to start things because they are tired, 74% struggled to finish things because they are tired and 78% reported limiting their social activities due to their fatigue. Most patients (69%) also reported feeling some level of frustration due to tiredness preventing them from doing what they want to do, and 3% felt they could not do their usual activities at all. All the above results on anxiety and depression, pain and discomfort and fatigue were relatively similar across all regions, with EU5 generally reporting a slightly lower frequency. Conclusion Chronic kidney disease (CKD) such as C3G places a substantial burden on patients’ QoL. Living with C3G has a clear impact on all aspects of the patients’ lives, encompassing both an emotional impact (e.g., anxiety/depression and frustration), as well as a physical impact (e.g., pain/discomfort, mobility and fatigue). More efficacious treatment options are needed to treat the cause of C3G to improve patients’ daily lives, increase their QoL, and to reduce the impact of living with C3G.

#457 Sparsentan has direct effects on the glomerular capillary wall to attenuate increased permeability after exposure to nephrotic syndrome plasma

Abstract Background and Aims The glomerular endothelial glycocalyx (eGlx), a luminal layer of proteoglycans, glycoproteins and glycolipids, forms the first part of the glomerular filtration barrier (GFB). Nephrotic syndrome (NS) describes a group of pathologies of the renal glomerulus that result in proteinuria and is associated with glomerular endothelial dysfunction. Current treatments are broad and non-specific. Sparsentan is a single-molecule dual endothelin type-A and angiotensin II type 1 receptor antagonist that has received accelerated approval in the United States for the reduction of proteinuria in adults with IgA nephropathy at high risk of disease progression. Our validated glomerular permeability assay directly measures the albumin permeability (Ps’alb)of capillary loops within individually trapped glomeruli [1]. This ex vivo assay is independent of haemodynamic factors and tubular albumin handling – factors known to affect urine protein concentrations. This work examines whether sparsentan could reduce glomerular albumin permeability in NS, by preserving the eGlx to maintain the GFB. Method Human NS plasma samples were collected under ethical consent from 3 patients that had undergone plasma exchange from periods when they were in relapse (RL), or subsequent remission (RM). Adult male Sprague Dawley rats (175–200 g) were perfused with 4% Ringer BSA solution. Glomeruli were isolated on ice by graded sieving from the cortex of each kidney. Glomeruli were incubated, in the presence of AF488-conjugated BSA (AF488-BSA, 30 μg/ml) and R18 (36.5 μg/ml), with 10% plasma from NS patients for 1 hour, and simultaneously treated with sparsentan (0.1 μM, 1 μM and 10 μM) or vehicle. The glomerular Ps’alb assay was used to measure changes in albumin permeability. We applied a fluorescence profile peak-to-peak confocal imaging technique to treated glomeruli to assess glomerular eGlx thickness [2]. Results Human NS patients in RL had a significantly greater proteinuria compared to RM (RL, 10, 000 ± 1, 354 mg/g; RM, 95.3 ± 59.7 mg/g, P = 0.017). Incubation of rat glomeruli with RL plasma induced a significant increase in Ps’alb (RM+vehicle, 6.0 × 10−7 ± 0.12 × 10−7 cm/s; RL+vehicle, 10.9 × 10−7 ± 0.84 × 10−7 cm/s, P &amp;lt; .001) with a significant reduction in glomerular eGlx thickness (RM+vehicle, 210 ± 21.2 nm; RL+vehicle, 109 ± 7.9 nm, P = .027), compared to rat glomeruli incubated with paired RM plasma. Sparsentan-treated RL incubated glomeruli were protected from both the increase in Ps’alb (RL+spars 10 µM, 6.3 × 10−7 ± 0.19 × 10−7 cm/s, P &amp;lt; .001) and the loss in glomerular eGlx (RL+spars 10 µM, 222 ± 8.5 nm, P = .013), to a level comparable to RM incubated glomeruli. The effect of sparsentan on Ps’alb was dose dependent (RL+spars 1 µM, 8.0 × 10−7 ± 0.46 × 10−7 cm/s; RL+spars 0.1 µM, 9.6 × 10−7 ± 0.22 × 10−7 cm/s) with Ps’alb changes correlating inversely with glomerular eGlx thickness (r² = 0.75, P &amp;lt; .0001). In RM glomeruli, sparsentan alone had no effect on Ps’alb compared with vehicle (RM+spars 10 µM, 6.2 × 10−7 ± 0.25 × 10−7 cm/s, P = .590), suggesting no effect on otherwise healthy capillaries. Conclusion We have shown that dual inhibition of endothelin and angiotensin receptors, with sparsentan, preserves the glomerular eGlx resulting in normalised glomerular permeability in NS. These findings suggest that the direct action of sparsentan on the GFB could help maintain barrier integrity in NS, in particular by glycocalyx protection.

#1021 A phase 3 randomized controlled trial of ravulizumab in adult patients with IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) includes the deposition of immune complexes in the kidney and activation of the complement system. Complement components, including C5a (anaphylatoxin) and C5b-9 (membrane attack complex), are generated leading to mesangial inflammation and glomerular injury [1]. Ravulizumab, a humanized monoclonal antibody, is a long-acting complement C5 inhibitor that provides immediate, complete, and sustained inhibition of the terminal complement pathway, thereby targeting a key component of the pathophysiology of IgAN. A phase 2 study of ravulizumab (NCT04564339) demonstrated a rapid effect and significant reduction in proteinuria compared with placebo at week 26 (change from baseline in 24-hour urine protein to creatinine ratio [UPCR] –40.3% vs –10.9%), and treatment was well-tolerated [2]. This abstract describes the study design of the planned phase 3 trial of ravulizumab in adult patients with IgAN. Method This phase 3, randomized, double-blind, placebo-controlled trial (I CAN) will evaluate the efficacy and safety of ravulizumab (IV; weight-based dosing Q8W) in adults with IgAN. Eligibility criteria include a diagnosis of primary IgAN based on kidney biopsy at any point, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at screening, and UPCR ≥0.75 g/g or urine protein ≥1.0 g/day (Table 1). The study consists of a 6-week screening period, followed by randomization (1:1) of participants to ravulizumab or placebo and a 2-year blinded treatment period (Fig. 1); all patients receive a stable and maximally tolerated dose of renin-angiotensin system inhibitor therapy. Approximately 450 patients will be randomized, stratified by proteinuria (&amp;lt;2 g/g vs ≥2 g/g), eGFR (&amp;lt;45 vs ≥45 mL/min/1.73 m2), and SGLT2i use (yes/no). The co-primary endpoints are change from baseline to week 34 in 24-hour UPCR evaluated on the log scale and the annualized total eGFR slope over 106 weeks. The sample size for the proteinuria endpoint of n = 204 will provide ∼90% power to detect a 35% relative treatment effect in UPCR at week 34 at a one-sided significance level of 0.005. The total sample size of n = 450 for the eGFR endpoint will provide ∼90% power to detect a difference in total annualized eGFR slope of 2.2 mL/min/1.73 m2 at week 106 at a one-sided significance level of 0.025. An open-label exploratory cohort (n = 20) with eGFR 20-29 mL/min/1.73 m2 and with kidney biopsy within 6 months of or during screening will be enrolled and analyzed separately from the main cohort. At completion of the blinded treatment period, all study participants will have the option to enter an open-label ravulizumab access period for up to 2 years. Results The co-primary endpoints are the change in 24-hour UPCR at week 34 and the annualized total eGFR slope over 106 wks. Secondary and exploratory endpoints include change in 24-hour UPCR at weeks 10, 26, 50, and 106, a composite kidney failure endpoint over 106 weeks, reduction in 24-hour UPCR ≥50% from baseline, time to UPCR &amp;lt;1 g/g and &amp;lt;0.3 g/g, and patient reported outcomes on fatigue, quality of life, and work-related productivity. Safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics will be evaluated. Conclusion Through immediate, complete, and sustained inhibition of C5, ravulizumab targets the pathophysiology of IgAN and has the potential to provide a disease modifying treatment option. This pivotal phase 3 study (I CAN) will evaluate the efficacy of ravulizumab in patients with IgAN who are at high risk of disease progression. The trial will evaluate effects on proteinuria and eGFR that may translate to long term kidney function preservation and provide a rapidly acting treatment option for patients living with IgAN.

Progression of adenomyosis: Rate and associated factors.

To evaluate the rate of disease progression and the factors associated with such progression in patients with an ultrasound diagnosis of adenomyosis. This was a single center, prospective, observational, cohort study performed at a tertiary referral center. Patients who obtained an ultrasound diagnosis of adenomyosis from May 2022 to August 2022 were recruited. Demographic, clinical and ultrasound data were recorded at the first visit (T0) and after 12 months (T1) for enrolled patients and compared between T0 and T1. The study population was divided in two groups according to progression (increase in uterine volume >20%) or stability/regression (decrease or increase in uterine volume ≤20%) of adenomyosis at T1. Primary study outcome was the rate of adenomyosis progression, while secondary study outcome was the association of adenomyosis progression with demographic and clinical factors. Post hoc subgroups analyses for primary and secondary study outcomes were performed based on hormonal therapy (untreated and treated). A total of 221 patients were enrolled in the study, with no significant difference in terms of baseline data among the two study groups and no patients were lost to follow-up. The overall rate of adenomyosis progression was 21.3% (47/221 patients). The rate was 30.77% in hormonally untreated women, and 18.34% in hormonally treated women. Progression was associated with the presence of focal adenomyosis of the outer myometrium (P = 0.037), moderate to severe dysmenorrhea (P = 0.001), chronic pelvic pain (P = 0.05), dyschezia (P = 0.05), and worsening of chronic pelvic pain (P = 0.04) at T1. Adenomyosis showed a rate of disease progression of 21.3% at the 12-month follow-up (30.77% in hormonally untreated women, and 18.34% in hormonally treated women). The presence and/or worsening of painful symptoms, such as severe dysmenorrhea, dyschezia and chronic pelvic pain, as well as the presence focal adenomyosis of the outer myometrium, might help identify patients at higher risk of disease progression and tailor their follow-up.

Predicting amyloid-PET and clinical conversion in apolipoprotein E ε3/ε3 non-demented individuals with multidimensional factors.

The apolipoprotein E (APOE) ε4 is a well-established risk factor of amyloid-β (Aβ) in Alzheimer's disease (AD). However, because of the high prevalence of APOE ε3, there may be a large number of people with APOE ε3/ε3 who are non-demented and have Aβ pathology. There are limited studies on assessing Aβ status and clinical conversion in the APOE ε3/ε3 non-demented population. Two hundred and ninety-three non-demented individuals with APOE ε3/ε3 from ADNI database were divided into Aβ-positron emission tomography (Aβ-PET) positivity (+) and Aβ-PET negativity (-) groups using cut-off value of >1.11. Stepwise regression searched for a single or multidimensional clinical variables for predicting Aβ-PET (+), and the receiver operating characteristic curve (ROC) assessed the accuracy of the predictive models. The Cox regression model explored the risk factors associated with clinical conversion to mild cognitive impairment (MCI) or AD. The results showed that the combination of sex, education, ventricle and white matter hyperintensity (WMH) volume can accurately predict Aβ-PET status in cognitively normal (CN), and the combination of everyday cognition study partner total (EcogSPTotal) score, age, plasma p-tau 181 and WMH can accurately predict Aβ-PET status in MCI individuals. EcogSPTotal score were independent predictors of clinical conversion to MCI or AD. The findings may provide a non-invasive and effective tool to improve the efficiency of screening Aβ-PET (+), accelerate and reduce costs of AD trial recruitment in future secondary prevention trials or help to select patients at high risk of disease progression in clinical trials.

Risk Score Model for Predicting COVID-19 Progression in Iranian Patients: Development and Validation Study

Background: The recent novel coronavirus disease 2019 (COVID-19) pandemic has underlined the importance of risk score models in public health emergencies. This study aimed to develop a risk prediction score to identify high-risk hospitalized patients for disease progression on admission. Methods: This prospective cohort study included 171 COVID-19 patients, identified through the reverse transcription polymerase chain reaction test, admitted to Bohlool Hospital in Gonabad City, Iran, between April 4 and June 5, 2021. The patients’ demographic, clinical, and laboratory data were collected upon admission, and clinical outcomes were monitored until the end of the study. The discovery dataset (80% of the data) was used to develop the risk score model based on clinical and laboratory features and patient characteristics to predict COVID-19 progression. An additive risk score model was developed based on the regression coefficients of the significant variables in a multiple logistic regression model. The performance of the risk score model was evaluated on the validation dataset (20% of the data) using the receiver operating characteristic (ROC) curve. Statistical analyses were performed with SPSS software, version 21. Results: The Mean±SD for age of participants was 59.54±20.52 years, and 48.6% were male. Most patients (82.5%) fully recovered or showed improvement, while 5.2% experienced disease progression and 12.3% died. Three variables, interleukin-6, neutrophil-to-lymphocyte ratio, and lung involvement, were found to be significant in predicting risk, with a good discriminatory ability, having an area under the ROC curve of 0.970 (95% CI, 0.935%, 1.00%) in the discovery set and 0.973 (95% CI, 0.923%, 1.00%) in the validation set. Conclusion: The developed risk score model in this study can be used as a clinical diagnostic tool to identify COVID-19 patients at higher risk of disease progression and aid in informed decision-making and resource utilization in similar situations, such as respiratory disease outbreaks in the post-corona era.

Systemic inflammatory autoimmune disease before allogeneic hematopoietic stem cell transplantation is a risk factor for death in patients with myelodysplastic syndrome or chronic myelomonocytic leukemia.

Myelodysplastic syndrome (MDS) is well known to be complicated by systemic inflammatory autoimmune disease (SIADs). However, it remains unclear how the prognosis after allogenic hematopoietic stem cell transplantation (allo-HSCT) in patients with MDS is impacted by SIADs that occur before allo-HSCT. Therefore, we hypothesized that SIADs before allo-HSCT may be a risk factor for negative outcomes after allo-HSCT in patients with MDS. We conducted a single-center, retrospective, observational study of sixty-nine patients with MDS or chronic myelomonocytic leukemia who underwent their first allo-HCT. Fourteen of the patients had SIADs before allo-HSCT. In multivariate analysis, the presence of SIADs before allo-HSCT was an independent risk factor for overall survival (HR, 3.36, 95% confidence interval: 1.34-8.42, p = 0.009). Endothelial dysfunction syndrome was identified in five of 14 patients with SIADs who required immunosuppressive therapy or intensive chemotherapy, and notably, all patients with uncontrollable SIADs at allo-HSCT developed serious endothelial dysfunction syndrome and died in the early phase after allo-HSCT. The development of SIADs in the context of MDS is thought to reflect the degree of dysfunction of hematopoietic cells in MDS and suggests a higher risk of disease progression. In addition, MDS patients with SIADs before allo-HSCT are considered to be at higher risk of endothelial dysfunction syndrome because of preexisting vascular endothelial dysfunction due to SIADs. In conclusion, SIADs before allo-HSCT constitute an independent risk factor for death in MDS patients undergoing allo-HSCT.

Conventional Cytogenetic Analysis and Array CGH + SNP Identify Essential Thrombocythemia and Prefibrotic Primary Myelofibrosis Patients Who Are at Risk for Disease Progression.

The Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are a heterogeneous group of clonal hematopoietic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (prePMF). In this study, we retrospectively reviewed the karyotypes from conventional cytogenetics (CC) and array Comparative Genomic Hybridization + Single Nucleotide Polymorphism (aCGH + SNP) in patients with ET or prePMF to determine whether the combined analysis of both methodologies can identify patients who may be at a higher risk of disease progression. We performed a comprehensive genomic review on 169 patients with a clinical diagnosis of ET (154 patients) or prePMF (15 patients). Genomic alterations detected by CC or array-CGH + SNP were detected in 36% of patients. In patients who progressed, 68% had an abnormal genomic finding by either technology. There was a shorter progression-free survival (PFS) among patients who were cytogenetically abnormal or who were cytogenetically normal but had an abnormal aCGH + SNP result. Leveraging the ability to detect submicroscopic copy number alterations and regions of copy neutral-loss of heterozygosity, we identified a higher number of patients harboring genomic abnormalities than previously reported. These results underscore the importance of genomic analysis in prognostication and provide valuable information for clinical management and treatment decisions.

The Efficacy and Safety of Reduced-Dose Oral Methylprednisolone in High-Risk Immunoglobulin A Nephropathy

IntroductionThe Therapeutic Effects of Steroids in IgA Nephropathy Global (TESTING) study reported that methylprednisolone reduces the risk of major kidney events in individuals with IgA nephropathy at high risk of disease progression compared to supportive care alone but is associated with increased serious adverse events (SAEs) primarily with full-dose therapy. The risk-benefit balance of the reduced-dose methylprednisolone regimen is examined in this pre-specified analysis of the reduced-dose cohort of the TESTING trial. MethodsBetween 2017-2019, patients with IgA nephropathy, proteinuria ≥1g/day despite 3 months of renin-angiotensin-system blockade and estimated glomerular filtration rate (eGFR) 30-120mL/min/1.73m2 were randomised to reduced-dose methylprednisolone 0.4mg/kg/day or placebo. The primary outcome was a composite of a 40% eGFR decline, kidney failure or death due to kidney disease. Results241 participants were randomised and followed-up for a median of 2.5 years (mean age 37 years, baseline eGFR 65mL/min/1.73m2, proteinuria 2.48g/day). Methylprednisolone was associated with fewer primary outcome events compared to placebo (7/121 vs 22/120, HR 0.24; 95% CI, 0.10-0.58, P = 0.002), lowered proteinuria and reduced eGFR rate of decline from baseline. The mean difference between methylprednisolone and placebo in proteinuria and eGFR from baseline was -1.15g/day and 7.9mL/min/1.73m2 (P <0.001) at 12 months respectively, but these benefits were lost over time. There were 7 vs 3 SAEs in the methylprednisolone vs placebo group (HR 1.97; 95% CI, 0.49-7.90) including 5 vs 2 infections. ConclusionReduced-dose methylprednisolone is effective in improving kidney outcomes in high-risk IgA nephropathy, however, is associated with a modestly higher number of SAEs compared to placebo.

Nirmatrelvir-Ritonavir Reduced Mortality in Hospitalized Patients with COVID-19 During the Omicron Outbreak: Real-World Evidence from Beijing.

The efficacy of nirmatrelvir-ritonavir for hospitalized patients with COVID-19 has not been fully established. We conducted a retrospective analysis of hospitalized COVID-19 patients with high risk for disease progression at Beijing Chaoyang Hospital from October 15, 2022, to March 31, 2023. Patients ≥18 years old who were hospitalized with COVID-19 within 5 days of symptom onset were included. Baseline data were obtained from the routine electronic health record database of the hospital information system. Outcomes were monitored at 28 days via electronic medical record reviews or telephone interviews. We identified 1120 patients hospitalized with COVID-19 during the study period. After exclusions, 167 nirmatrelvir-ritonavir users and 132 controls were included. 28-day all-cause mortality rate was 12.0% (20/167) in the nirmatrelvir-ritonavir group, versus 22.7% (30/132) in the control group (unadjusted log-rank p = 0.010; HR = 0.49, 95% confidence interval [CI] = 0.28-0.86, IPTW-adjusted HR = 0.58, 95% CI = 0.40-0.86). The 28-day disease progression rates did not differ between the two groups (unadjusted HR = 0.59, 95% CI = 0.34-1.02, IPTW-adjusted HR = 0.73, 95% CI = 0.50-1.06). Nirmatrelvir-ritonavir significantly reduced all-cause mortality and disease progression within 28 days among patients aged ≥65 years without ≥2 vaccine doses. We found significantly reduced all-cause mortality in the nirmatrelvir-ritonavir group, particularly in elderly patients who were incompletely vaccinated. Future randomized controlled studies are needed to validate our findings.