High Risk Of Disease Progression Research Articles

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.

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.

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.

Epidemiology of NAFLD – Focus on diabetes

There is increasing appreciation of the complex interaction between nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D) and insulin resistance. Not only is the prevalence of NAFLD disease high among patients with T2D, the liver disease is also more progressive. Currently, the global prevalence of NAFLD in the general population (2016–2019) is 38 %. The prevalence of T2D among those with NAFLD is approximately 23 % while the prevalence of NAFLD among those with T2D can be as high as 70 %. The prevalence of nonalcoholic steatohepatitis (NASH) is approximately 7 % in the general population and 37 % among patients with T2D. Globally, the MENA and Latin America regions of the world appear to have the highest burden of both NAFLD and T2D. Compared to those with NAFLD but without T2D, those with NAFLD and T2D are at a much higher risk for disease progression to cirrhosis and for decompensated cirrhosis, hepatocellular carcinoma, and all-cause mortality. Given that highly effective new treatments are available for T2D, high risk NAFLD with T2D should be considered for these regimens. This requires implementation of risk stratification algorithms in the primary care and endocrinology practices to identify those patients at highest risk for adverse outcomes.

A nomogram based on contrast-enhanced ultrasound for evaluating the glomerulosclerosis rate in transplanted kidneys.

A high rate of glomerulosclerosis serves as an important signal of poor response to treatment and a high risk of disease progression or adverse prognosis in transplanted kidneys. We hypothesized that contrast-enhanced ultrasound (CEUS) could serve as a novel imaging biomarker in the early prediction of glomerulosclerosis rate by evaluating renal allograft microcirculation. A retrospective analysis was performed on 143 transplanted kidney recipients with confirmed pathology, including 100 in the training group and 43 in the validation group. All patients underwent conventional ultrasound (CUS) and CEUS examinations. The patients were divided into two groups: those with >50% glomerulosclerosis and those with ≤50% glomerulosclerosis. The nomograms derived from independent predictors identified by multivariate logistic analysis were assessed using receiver operating characteristic (ROC) curve analysis, 1,000 bootstrap resamples, calibration curves, and decision curve analysis (DCA). The patients with >50% glomerulosclerosis and those with ≤50% glomerulosclerosis showed statistically significant differences in CEUS parameters, including in peak intensity (PI) (25 vs. 30; P<0.001), absolute time to peak (ATTP) (10 vs. 9; P=0.004), and time to peak (TTP) (22 vs. 19.5; P=0.026). Multivariate analysis revealed that PI [odds ratio (OR) =0.852; 95% confidence interval (CI): 0.737-0.986], peak systolic velocity (PSV) of the interlobar artery (OR =0.850; 95% CI: 0.758-0.954), cortical echogenicity (OR =38.429; 95% CI: 3.695-399.641), and time since transplantation (OR =1.017; 95% CI: 1.006-1.028) were independent predictors of whether the glomerulosclerosis rate was >50% and were incorporated into the construction of a nomogram. The area under the curve (AUC) of the nomogram in the training and validation groups was 0.914 (95% CI: 0.840-0.960) and 0.909 (95% CI: 0.781-0.975), respectively, with a bootstrap resampling AUC of 0.877. The calibration curve and DCA confirmed the diagnostic performance of the nomogram model. The nomogram, which combined CUS, CEUS, and clinical indicators, exhibited notable predictive efficacy for the glomerulosclerosis rate in transplanted kidneys, thereby demonstrating the potential to improve clinical decision-making.

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.

Genomic profiling of mycosis fungoides identifies patients at high risk of disease progression

AbstractMycosis fungoides (MF) is the most prevalent primary cutaneous T-cell lymphoma, with an indolent or aggressive course and poor survival. The pathogenesis of MF remains unclear, and prognostic factors in the early stages are not well established. Here, we characterized the most recurrent genomic alterations using whole-exome sequencing of 67 samples from 48 patients from Lille University Hospital (France), including 18 sequential samples drawn across stages of the malignancy. Genomic data were analyzed on the Broad Institute’s Terra bioinformatics platform. We found that gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), or mutations in JUNB and TET2 are associated with high-risk disease stages. Furthermore, gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), and del6q16.3 (TNFAIP3) are coupled with shorter survival. Del6q16.3 (TNFAIP3) was a risk factor for progression in patients at low risk. By analyzing the clonal heterogeneity and the clonal evolution of the cohort, we defined different phylogenetic pathways of the disease with acquisition of JUNB, gain10p15.1 (IL2RA and IL15RA), or del12p13.1 (CDKN1B) at progression. These results establish the genomics and clonality of MF and identify potential patients at risk of progression, independent of their clinical stage.

A universal plasma metabolites-derived signature predicts cardiovascular disease risk in MAFLD

BackgroundMetabolic associated fatty liver disease (MAFLD) is a novel concept proposed in 2020, which is more practical for identifying patients with fatty liver disease with high risk of disease progression. Fatty liver is a driver for extrahepatic complications, particularly cardiovascular diseases (CVD). Although the risk of CVD in MAFLD could be predicted by carotid ultrasound test, a very early stage prediction method before the formation of pathological damage is still lacking. MethodsStool microbiomes and plasma metabolites were compared across 196 well-characterized participants encompassing normal controls, simple MAFLD patients, MAFLD patients with carotid artery pathological changes, and MAFLD patients with diagnosed coronary artery disease (CAD). 16S rDNA sequencing data and untargeted metabolomic profiles were interrogatively analyzed using differential abundance analysis and random forest (RF) machine learning algorithm to identify discriminatory gut microbiomes and metabolomic. ResultsCharacteristic microbial changes in MAFLD patients with CVD risk were represented by the increase of Clostridia and Firmicutes-to-Bacteroidetes ratios. Faecalibacterium was negatively correlated with mean-intima-media thickness (IMT), TC, and TG. Megamonas, Bacteroides, Parabacteroides, and Escherichia were positively correlated with the exacerbation of pathological indexes. MAFLD patients with CVD risk were characterized by the decrease of lithocholic acid taurine conjugate, and the increase of ethylvanillin propylene glycol acetal, both of which had close relationship with Ruminococcus and Gemmiger. Biotin l-sulfoxide had positive correlation with mean-IMT, TG, and weight. The general auxin pesticide beta-naphthoxyacetic acid and the food additive glucosyl steviol were both positively correlated with the increase of mean-IMT. The model combining the metabolite signatures with 9 clinical parameters accurately distinguished MAFLD with CVD risk in the proband and validation cohort. It was found that citral was the most important discriminative metabolite marker, which was validated by both in vitro and in vivo experiments. ConclusionsSimple MAFLD patients and MAFLD patients with CVD risk had divergent gut microbes and plasma metabolites. The predictive model based on metabolites and 9 clinical parameters could effectively discriminate MAFLD patients with CVD risk at a very early stage.

Abstract 6684: Impact of fecal microbiome on the efficacy of neoadjuvant chemo-immunotherapy and colitis adverse events: Findings from the NADIM II Trial

Abstract Introduction: The balance and composition of the gut microbiome play a pivotal role in modulating the host immune system, and they have been associated with survival outcomes in patients undergoing immunotherapy-based treatments and immune-related adverse events. In this study, our objective was to analyze the fecal microbiota of non-small-cell lung cancer (NSCLC) patients with locally advanced disease undergoing neoadjuvant chemo-immunotherapy (IO-CT). Methods and patients: Baseline stool samples were collected from 86 resectable stage IIIA/B NSCLC patients enrolled in the NADIM II clinical trial (NCT03838159). The patients were randomly assigned to receive either neoadjuvant nivolumab plus chemotherapy (CT) or CT alone. DNA extraction was performed using the QIAamp PowerFecal DNA Kit (Qiagen), and the samples were analyzed using the Ion AmpliSeq Microbiome Health Research assay (ThermoFisher). The NGS analysis utilized the AmpliSeq Microbiome Health w1.3 workflow. Alpha diversity was assessed using the Simpson and Chao1 Index. Results: Among the 86 collected stool samples, 77 were deemed valid for analysis. Bacteroides were the most common genus with a relative percentage (RP) of 18.9% ± 14.8 followed by Faecalibacterium (13.4% ± 7.8). The presence of bacteria from the genera Bifidobacterium, and Faecalibacterium was associated with improved progression-free survival (PFS) [HR = 0.4 (0.16-0.98), and HR = 0.08 (0.01-0.72), respectively] and overall survival (OS) [HR = 0.19 (0.06-0.62)], and HR = 0.04 [0.01-0.43], respectively), in the experimental arm. The detection of Faecalibacterium prausnitzii (validated by qPCR) was associated with improved PFS [HR = 0.17 (0.04-0.76)] and OS [HR = 0.05 (0.01-0.29)] in the experimental. On the other hand, detection of bacteria from the genera Synergistes, Lactobacillus, and Anaerotruncus was associated to higher risk of disease progression [HR = 9.9 (1.2-85), HR = 3.7 (1.5-9.1), and HR = 12 (1.4-110)] and death [HR = 51 (3.2-820), HR = 6.7 (2-23), and HR = 25 (2.3-280)] in this set of patients.In the entire cohort, patients whose samples were in the highest tertile of alpha diversity, had significantly prolonged PFS compared to those with intermediate or low diversity [HR = 0.39 (0.16-0.94)]. Finally, 25 colitis adverse events (CAE) occurred in 18 patients, including two Grade 3 (2.3%) and four Grade 2 (4.6%) events. A higher RP of Bacteroides were found in patients who did not suffer colitis events (P = 0.016), whereas higher RP of Coriobacterium were detected in patients who suffered CAE (P = 0.023). Conclusions: Our findings suggest that composition of the gut microbiome may play a crucial role in the effectiveness of neoadjuvant IO-CT in NSCLC patients. Specifically, the presence of F. prausnitzii may enhance the antitumor activity of these treatments. Citation Format: Roberto Serna-Blasco, Alejandro Rodriguez Festa, Sandra Sanz-Moreno, Lucía Robado de Lope, Pilar Mediavilla Medel, Ernest Nadal, Jose Luis González Larriba, Alex Martínez-Martí, Reyes Bernabé, Joaquim Bosch-Barrera, Joaquín Casal-Rubio, Virginia Calvo, Amelia Insa, Santiago Ponce, Noemí Reguart, Javier de Castro, Joaquín Mosquera, Manuel Cobo, Andrés Aguilar, Carlos Camps, Rafael López de Castro, Teresa Morán, Isidoro Barneto, Delvys Rodríguez-Abreu, Carlos Aguado de la Rosa, Ramón Palmero, Florentino Hernando-Trancho, Javier Martín-López, Alberto Cruz-Bermúdez, Bartomeu Massuti, Miguel Ángel Molina Vila, Atocha Romero, Mariano Provencio. Impact of fecal microbiome on the efficacy of neoadjuvant chemo-immunotherapy and colitis adverse events: Findings from the NADIM II Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6684.

Prognostic Significance of the Cribriform Pattern in Prostate Cancer: Clinical Outcomes and Genomic Alterations.

Given the diverse clinical progression of prostate cancer (PC) and the evolving significance of histopathological factors in its management, this study aimed to explore the impact of cribriform pattern 4 (CP4) on clinical outcomes in PC patients and examine its molecular characteristics. This retrospective study analyzed data from The Cancer Genome Atlas (TCGA) database and included PC patients who underwent radical prostatectomy (RP) and had pathology slides available for the assessment of CP4. A multivariable competing risk regression analysis was used to assess the association between CP4 and progression-free survival (PFS) while adjusting for established PC prognostic factors. The frequency of genomic alterations was compared between patients with and without CP4 using the Fisher's exact test. Among the 394 patients analyzed, 129 (32.74%) had CP4. After a median follow-up of 40.50 months (IQR: 23.90, 65.60), the presence of CP4 was significantly associated with lower PFS (AHR, 1.84; 95% CI, 1.08 to 3.114; p = 0.023) after adjusting for covariates. Seven hub genes-KRT13, KRT5, KRT15, COL17A1, KRT14, KRT16, and TP63-had significantly lower mRNA expression levels in patients with CP4 compared to those without. PC patients with CP4 have distinct genomic alterations and are at a high risk of disease progression following RP. Therefore, these patients may benefit from additional post-RP treatments and should be the subject of a prospective randomized clinical trial.

Are changes in patient-reported outcomes prognostic for diffuse large B-Cell lymphoma survival? Results from the GOYA trial.

In this hypothesis-generating analysis, we examined whether longitudinal changes in patient-reported outcomes (PROs), such as symptoms, over time would be prognostic for progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who were newly treated with obinutuzumab (G) in combination with CHOP (G-CHOP) or rituximab (R) with CHOP (R-CHOP), in the GOYA Phase 3 trial (NCT01287741). Our results show that from the study baseline to cycle 3day 1, every 1-point increase (worsening) in fever symptoms was associated with a 41% higher risk of death (hazard ratio [HR], 1.41; P = 0.01). Every 1-point increase (worsening) in lumps or swelling symptoms was associated with a 27% higher risk of disease progression or death (PFS events) (HR, 1.27; P = 0.01) and a 29% higher risk of death (OS events) (HR, 1.29; P = 0.02). No significant associations were observed between survival and changes in other symptoms, such as itching. Our study suggests that changes in some PROs are related to survival in DLBCL patients.

The 40-gene Expression Profile (40-GEP) Test Identifies Cutaneous Squamous Cell Carcinoma (cSCC) Patients at High Risk of Metastasis within Lower-Staged Tumors to Better Guide Treatment Decisions

Introduction- The development of metastases has a profound impact on cSCC patient survival. Lower-stage tumors are those that lack factors that portend higher risk for disease progression and therefore not typically considered for increased surveillance or treatment. However, up to one-third of all metastatic events have been reported for patients originally staged as T1. The 40-GEP test is validated to accurately classify risk for regional and/or distant metastasis in patients with primary cSCC with at least one high-risk factor.  The current study investigated whether the 40-GEP test could independently improve identification of lower-staged tumors at increased risk of metastasis. &#x0D; Methods- In an IRB-approved, retrospective, multi-center study, primary tumor tissue and associated clinical data from patients with cSCC and one or more clinicopathologic risk factors (n=897) were collected. Within this overall cohort, lower Brigham and Women’s Hospital (BWH) T-staged samples (n=444 T1 and n=335 T2a) were evaluated by Kaplan-Meier survival analysis to determine metastasis-free survival (MFS) according to 40-GEP risk class (Class 1-low metastatic risk; Class 2A-higher risk; Class 2B-highest risk).&#x0D; Results- There was a total of 118 metastatic events in the overall cohort, of which 25% (29/118) and 38% (45/118) occurred in BWH T1 and T2a, respectively. BWH T1 tumors had an overall event rate of 6.5% (29/444), with T1/Class 2B tumors having a 5.1-fold increased event rate of 33.3%. BWH T2a tumors had an overall event rate of 13.4% (45/335), with T2a/Class 2B tumors having a 2.7-fold increased event rate of 36.4%. Stratification by the 40-GEP test resulted in significantly different metastasis rates across all three 40-GEP classes within both the T1 and T2a subsets (log-rank tests, p&lt;0.0001 each subset). &#x0D; Conclusion- Within a cohort of cSCC patients considered lower risk by current staging alone, the 40-GEP identified patients with a substantial increase in metastatic risk.  The observed rates of metastasis over 10% and 20% are clinically actionable for nodal staging or postoperative adjuvant radiation, respectively. Combining clinicopathologic risk assessment with individual biologic risk, as provided by the 40-GEP test, improves the accuracy of risk assessment used clinically as the basis of treatment decisions.

Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER.

Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium-glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood. The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02-1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72-0.96) and without previous MI (HR 0.76, 95% CI 0.68-0.85; pinteraction  = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI. History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI.

Association between comorbidities and survival in patients with metastatic urothelial carcinoma treated with pembrolizumab.

This study aims to investigate the relationship between comorbidities and survival in patients with mUC treated with pembrolizumab as a second-line treatment. From February 2018 to October 2021, we analyzed the data of 185 consecutive patients with metastatic UC who received pembrolizumab as second-line therapy at The Jikei University Hospital and five affiliated hospitals. We used the Charlson Comorbidity Index (CCI) to assess the comorbidities. The outcomes of interest were progression-free survival (PFS) and overall survival (OS). To compare the survival differences, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and the IPTW-adjusted Cox regression hazards model were used. After IPTW adjustment, patient characteristics were well-balanced between patients with high CCI and those with low CCI. The IPTW-adjusted Kaplan-Meier curves of PFS and OS based on CCI revealed that the patients with high CCI (2 or more) had a shorter PFS (median, 1.6 vs. 2.8months) and a shorter OS (median, 12.4 vs. 18.8months) (0-1). Similarly, in the IPTW-adjusted Cox regression hazards model, patients with high CCI had significantly shorter PFS [HR, 1.84 (95% CI 1.26-2.68; p = 0.002)] and OS [HR, 1.98 (95% CI 1.20-3.27; p = 0.008)] than those with lower CCI. High CCI was associated with a higher risk of disease progression as well as overall mortality in mUC patients treated with second-line pembrolizumab.

Searching The New Culprit of Optic Neuritis: The Role of Vitamin D

Abstract&#x0D; Introduction : Low vitamin D status has long been associated in multiple sclerosis patient with higher risk of disease progression and frequent relapses. Vitamin D plays an important role in modulating the immune process responsible for demyelination. To this date, the study on vitamin D deficiency in optic neuritis case is still rare.&#x0D; Case Illustration : Female, 20 years old, presenting with bilateral sudden visual loss since 1 week prior. The patient looked relatively pale and complained of accompanying headache and myalgia. Visual acuity in both eyes were light perception with dilated pupils and posterior segment showing optic disc swelling. CBC, infection and autoimmune screening came within normal limit and brain MRI further confirmed the presence of optic neuritis. The patient was given high dose intravenous steroid but showed no improvement. Later, she was screened for nutrient deficiency and found sign of low serum 25-hydroxyvitamin D. After one week of oral supplementation and neuroprotective agents, her vision drastically improved to 6/6 in both eyes.&#x0D; Discussion : Vitamin D deficiency nowadays is getting more prevalent in high risk individuals with low dietary intake and sunlight exposure. Recent study found that mean serum vitamin D level were significantly lower in autoimmune optic neuritis (ON) and were associated with ON attack severity. Vitamin D sufficiency is associated with better inflammatory outcome and long term neurodegenerative measures in demyelinating diseases, as shown by improvement in RNFL thickness after attack.&#x0D; Conclusion : Screening for vitamin D deficiency is essential to consider in managing patient with atypical optic neuritis.

Mutational signature and prognosis in adenocarcinoma of bladder.

655 Background: Adenocarcinoma of bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here we aim to reveal mutational and transcriptomic landscapes of adenocarcinoma of bladder and their relationship with prognosis. Methods: Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of bladder were included. These included 16 patients with primary bladder adenocarcinomas and 7 patients with urachal adenocarcinoma. Whole exome sequencing, whole genome sequencing, bulk RNA-Seq and single-cell RNA-Seq were conducted for the specimens. Correlation analysis, survival analysis and t tests were also performed. Results: Prevalent T&gt;A substitutions were observed among somatic mutations, and major tri-nucleotide contexts included 5′-CTC-3′and 5′-CTG-3′. This pattern was mainly contributed by COSMIC Signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes also enriched KEGG term “chemical carcinogenesis”. Transcriptomic analysis implied high immune infiltration and luminal-like feature in majority of samples. Interestingly, a small fraction of samples with APOBEC-derived mutational signature exhibited higher risk of disease progression compared with samples with only chemical carcinogen-related signature, confirming molecular and prognosis heterogeneity in bladder adenocarcinoma. Conclusions: This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and chemical carcinogen-related mutational signature indicates good prognosis in adenocarcinoma of bladder.

Sparsentan is superior to losartan in the gddY mouse model of IgA nephropathy.

The mechanism leading to the development of IgA nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation, and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist (DEARA), recently received accelerated approval in United States for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. Four-week-old gddY mice were given control chow, chow containing sparsentan, or drinking water containing losartan until 12 or 20 weeks old. Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, ETAR, and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared to AT1R antagonism alone.

Genomic classification and outcomes of young patients with polycythemia vera and essential thrombocythemia according to the presence of splanchnic vein thrombosis and its chronology

To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9–4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4–24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.

P962 Clinical and endoscopic remission at 3 months after Acute Severe Ulcerative Colitis is predictive of maintenance therapy outcomes at 12 months - Results from PREDICT UC

Abstract Background The optimal maintenance regimen after rescue therapy for Acute Severe Ulcerative Colitis (ASUC) is unknown. We aimed to evaluate prospectively the impact of different maintenance regimens after successful infliximab (IFX) rescue, along with factors associated with Month 12 remission. Methods Clinical responders at 3 months from PREDICT UC, a randomised trial (NCT02770040) comparing standard and intensified IFX rescue strategies, were evaluated in this prospective cohort study up to Month 12. Maintenance therapies were as follows: (1) Thiopurine monotherapy (azathioprine or mercaptopurine) for thiopurine naïve patients or prior suboptimal thiopurine therapy (TP); (2) Combination thiopurine and IFX therapy 5mg/kg 8-weekly for thiopurine-experienced patients (IFX+TP combo); (3) IFX monotherapy 5mg/kg 8-weekly for thiopurine-intolerant patients (IFX mono). All patients received oral 5-aminosalicylates. Clinical and endoscopic assessments were performed at baseline (Month 3) and Month 12. Clinical remission was defined as a partial Mayo score of 0-1 and endoscopic remission as Mayo Endoscopic Score (MES) of 0-1. Results Of 138 patients randomised, 79 entered the maintenance phase. Of these, 56 (71%) received TP, 16 (20%) received IFX+TP combo and 7 (9%) received IFX mono. Baseline characteristics were similar across the 3 maintenance groups. At 12 months, 42 patients (53%) were in clinical remission, 44 patients (56%) were in endoscopic remission, and one patient underwent colectomy. The 3 maintenance groups had similar rates of clinical remission (TP 55%, IFX+TP combo 56%, IFX mono 29%; P=0.39) and endoscopic remission (TP 55%, IFX+TP combo 56%, IFX mono 57%; P=0.99) at 12 months. Clinical Remission On univariable and multivariable analysis, no factors were associated with clinical remission at 12 months, including baseline CRP, albumin, partial Mayo score, MES, UCEIS or maintenance strategy. Endoscopic Remission Factors associated with endoscopic remission at 12 months included baseline partial Mayo score of 0 (OR 3.36, 95% CI 1.24-9.10, P=0.017), MES of 0-1 (OR 3.48, 95% CI 1.08-11.27, P=0.037) and UCEIS of 0-1 (OR 3.30, 95% CI 1.24-8.76, P=0.016). However, a partial Mayo score cut-off of 0-1 did not reach significance (OR 3.46, P=0.09). No factors associated with endoscopic remission were identified on multivariable analysis. Conclusion In steroid-refractory ASUC patients who received IFX rescue, clinical and endoscopic remission at Month 3 were associated with endoscopic remission at Month 12, particularly among patients with greater depth of remission. Month 3 assessment helps identify patients at higher risk of disease progression for whom more intensive treatment may be required.