High Risk Of Disease Progression Research Articles

Estimating Transition Probabilities Across the Alzheimer's Disease Continuum Using a Nationally Representative Real-World Database in the United States.

Clinical Alzheimer's disease (AD) begins with mild cognitive impairment (MCI) and progresses to mild, moderate, or severe dementia, constituting a disease continuum that eventually leads to death. This study aimed to estimate the probabilities of transitions across those disease states. We developed a mixed-effects multi-state Markov model to estimate the transition probabilities, adjusted for 5 baseline covariates, using the Health and Retirement Study (HRS) database. HRS surveys older adults in the United States bi-annually. Alzheimer states were defined using the modified Telephone Interview of Cognitive Status (TICS-m). A total of 11,292 AD patients were analyzed. Patients were 70.8±9.0years old, 54.9% female, and with 12.0±3.3years of education. Within 1year from the initial state, the model estimated a higher probability of transition to the next AD state in earlier disease: 12.8% from MCI to mild AD and 5.0% from mild to moderate AD, but<1% from moderate to severe AD. After 10years, the probability of transition to the next state was markedly higher for all states, but still higher in earlier disease: 29.8% from MCI to mild AD, 23.5% from mild to moderate AD, and 5.7% from moderate to severe AD. Across all AD states, the probability of transition to death was<5% after 1year and>15% after 10years. Older age, fewer years of education, unemployment, and nursing home stay were associated with a higher risk of disease progression (p<0.01). This analysis shows that the risk of progression is greater in earlier AD states, increases over time, and is higher in patients who are older, with fewer years of education, unemployed, or in a nursing home at baseline. The estimated transition probabilities can provide guidance for future disease management and clinical trial design optimization, and can be used to refine existing cost-effectiveness frameworks.

NIS2+™, an optimisation of the blood-based biomarker NIS4® technology for the detection of at-risk NASH: A prospective derivation and validation study

NIS4® is a blood-based non-invasive test designed to effectively rule in/rule out at-risk non-alcoholic steatohepatitis (NASH), defined as non-alcoholic fatty liver disease activity score ≥4 and significant fibrosis (stage ≥2), among patients with metabolic risk factors. Robustness of non-invasive test scores across characteristics of interest including age, type 2 diabetes mellitus, and sex, and optimised analytical aspects are critical for large-scale implementation in clinical practice. We developed and validated NIS2+™, an optimisation of NIS4®, specifically designed to improve score robustness. A well-balanced training cohort (n= 198) included patients from the GOLDEN-505 trial. The validation (n= 684) and test (n= 2,035) cohorts included patients from the RESOLVE-IT trial. Well-matched subgroups were created to avoid potential confounding effects during modelling and analysis of score robustness. Models were trained using logistic regressions for at-risk NASH detection and compared using Bayesian information criteria. Performance of NIS2+™ was compared with that of NIS4®, Fibrosis-4, and alanine aminotransferase using area under the receiver operating characteristic curve, and robustness was analysed through score distribution. Using the training cohort to compare all combinations of NIS4® biomarkers, NIS2 (miR-34a-5p, YKL-40) was identified as the best combination of parameters. To correct for the sex effect on miR-34a-5p (validation cohort), sex and sex ∗ miR-34a-5p parameters were added, creating NIS2+™. In the test cohort, NIS2+™ exhibited a statistically higher area under the receiver operating characteristic curve (0.813) vs. NIS4® (0.792; p= 0.0002), Fibrosis-4 (0.653; p <0.0001), and alanine aminotransferase (0.699; p <0.0001). NIS2+™ scores were not affected by age, sex, BMI, or type 2 diabetes mellitus status, providing robust clinical performances irrespective of patient characteristics. NIS2+™ constitutes a robust optimisation of NIS4® technology for the detection of at-risk NASH. The development of non-invasive tests for accurate, large-scale detection of patients with at-risk non-alcoholic steatohepatitis (NASH; defined as NASH with non-alcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2) - who are at higher risk for disease progression and for developing liver-related life-threatening outcomes - is critical for identifying this patient population in the clinical setting and improving the screening process of NASH clinical trials. We report the development and validation of NIS2+™, a diagnostic test designed as an optimisation of NIS4® technology, a blood-based panel currently used to detect at-risk NASH in patients with metabolic risk factors. NIS2+™ showed improved performance for the detection of at-risk NASH compared with NIS4® and other non-invasive liver tests that was not impacted by patients' characteristics of interest, such as age, sex, type 2 diabetes mellitus, BMI, dyslipidaemia, and hypertension. This makes NIS2+™ a robust and reliable tool for the diagnosis of at-risk NASH among patients with metabolic risk factors, and an effective candidate for large-scale implementation in clinical practice and clinical trials.

Efficacy of Sotrovimab (SOT), Molnupiravir (MOL), and Nirmatrelvir/Ritponavir (N/R) and Tolerability of Molnupiravir in Outpatients at High Risk for Severe COVID-19.

The main goal of this study was to assess the potential clinical impact of an outpatient administration of available antivirals including SOT, N/R, and MOL to COVID-19 patients at high risk for disease progression. We conducted a retrospective analysis on 2606 outpatient individuals with mild to moderate COVID-19 at risk for disease progression, hospitalization, or death. After receiving either SOT (420/2606), MOL (1788/2606), or N/R (398/2606), patients were followed-up with regarding primary (hospitalization rate) and secondary (treatment and side effects) outcomes by phone. A total of 2606 patients were treated at the outpatient clinic (SOT: 420; N/R: 398; MOL: 1788). 3.2% of the SOT patients (1 ICU admission), 0.8% of the MOL patients (2 ICU admissions), and none of the N/R patients were hospitalized. 14.3% of the N/R patients reported strong to severe side effects, exceeding SOT (2.6%) and MOL (5%) patients. A reduction in COVID symptoms after the treatment was experienced by 43% of patients in both the SOT and MOL groups and by 67% of patients in the N/R group, respectively. Women had a higher chance of symptom improvement with MOL (OR 1.2, 95%CI 1.0-1.5). All antiviral treatment options effectively prevented hospitalization in high-risk COVID-19 patients and were well tolerated. Side effects were pronounced in patients with N/R.

COVID-19 hospitalized patients and oral changes: a case-control study.

To investigate the association between hospitalization for COVID-19 and oral changes, and to evaluate whether oral changes can indicate a higher risk of disease progression to death. This case-control study analyzed patients hospitalized (university hospital), including those in intensive care unit and clinical wards. The study group comprised 69 COVID-19 positive patients (PCR-test), while the control group included 43 COVID-19 negative patients. A dentist performed oral evaluations, and salivary samples were collected for calcium, phosphatase, and pH analysis. Sociodemographic data, hospitalization information, and hematological test results were collected from electronic-medical records. The presence of oral changes was assessed using chi-square tests, and the predicted risk of death was analyzed using binary logistic regression. COVID-19 positive patients had a significantly higher prevalence of oral changes compared to COVID-19 negative patients. The presence of any oral changes in COVID-19 positive patients indicated a 13-fold higher risk of mortality. "Bleeding ulcers," "pressure ulcers," and "angular cheilitis" were significantly associated with hospitalization for COVID-19. There may be an association between hospitalization for COVID-19 and the development of oral changes, including bleeding ulcers, pressure ulcers. and angular cheilitis. These oral changes may serve as potential indicator for disease progression an increased risk of death. COVID-19 hospitalized patients have a higher prevalence of oral changes, which indicate an increased risk of mortality. Oral medicine staff should be included in multidisciplinary teams to detect and treat these oral changes promptly.

Comparative effectiveness and safety for the treatments despite optimized renin-angiotensin system blockade among IgA nephropathy patients at high-risk of disease progression: A network meta-analysis of randomized controlled trials

ObjectiveApproximately 20–40% of IgA nephropathy patients would develop end-stage renal disease, for whom safety concerns remained a major setback when using conventional pharmaceutical treatments. Evidence is lacking for optimal selection of effective and safe pharmaceuticals to slow the disease progression. To compare the effectiveness and safety profile of different treatments despite optimized RAS blockade for IgA nephropathy patients at high-risk of disease progression. Study designPubMed, ScienceDirect and Web of science databases published from 1990 to March 18th, 2023 without language restriction. Immunosuppressant and cortico-steroid treatments were considered as two independent regimens. ResultsFifteen trials with 1,983 participants were evaluated for the occurrence of five outcomes. For ESRD, dapagliflozin was superior to placebo (RR: 0.30; 95% CI 0.11, 0.80), immunosuppressant (RR:0.14; 95% CI 0.02,0.81) and RAS (RR:0.10; 95% CI 0.01,0.69). Glucocorticoid was superior to placebo (RR: 0.71; 95%CI 0.52,0.99). For clinical remission, immunosuppressant was superior to placebo (RR: 2.71; 95%CI 1.16, 6.31) and RAS monotherapy (RR: 2.87; 95%CI 1.60, 5.17). For 50% reduction in 24 h proteinuria or UPCR, immunosuppressant was superior to placebo (RR: 2.71; 95%CI 1.16, 6.31) and RAS monotherapy (RR: 2.40; 95%CI 1.04, 5.55). For SAE, dapagliflozin was superior to glucocorticoid (RR: 0.22; 95%CI 0.09, 0.54), whereas glucocorticoid was inferior to placebo (RR: 2.91; 95%CI 1.39, 6.07). Cluster ranking showed dapagliflozin appeared to have the lowest SAE risk and the best comparative therapeutic efficacy in preventing ESRD. ConclusionsThe current findings highlighted dapagliflozin was a promising pharmaceutical treatment alternative to achieve optimal outcomes for IgA nephropathy patients at high risk of disease progression. RegistrationPROSPERO CRD42022374418.

Use of sotrovimab in vaccinated versus unvaccinated COVID-19 patients in a resource-limited emergency department during the omicron surge.

The treatment of outpatient COVID-19 patients at high risk of disease progression has been challenging, as both the virus and available therapeutics change. Here, we sought to evaluate the effect of vaccination status on the use of sotrovimab during the early phase of the Omicron surge. This was a retrospective observational study performed at El Centro Regional Medical Center, a rural hospital on the southern Californian border. The electronic medical record was queried for all emergency department (ED) patients who received an infusion of sotrovimab between January 6 and February 6, 2022. We obtained patient demographics, COVID-19 vaccination status, medical comorbidities, and whether patients returned to the ED within 30 days. We stratified our cohort according to vaccination status and performed a multivariable logistic regression model to evaluate the relationship between these factors. One hundred seventy patients received an infusion of sotrovimab in the ED. The patient cohort had a median age of 65 years, 78.2% were Hispanic, and obesity (63.5%) was the most common comorbidity. A total of 73.5% of patients were vaccinated against COVID-19. A total of 12/125 (9.6%) of vaccinated patients returned to the ED within 30 days, versus 10/45 (22.2%) in the unvaccinated cohort, which was statically significant (P=0.03). The presence of medical comorbidities was not associated with the primary outcome. Of patients who received sotrovimab, those who were vaccinated were less likely to return to the ED within 30 days compared to those who were unvaccinated. Given the effectiveness of the COVID-19 vaccination campaign, and with the emergence of new variants, it is unclear what role monoclonal antibody therapy should play in the treatment of outpatient COVID-19 patients.

Molnupiravir and Combination of Nirmatrelvir and Ritonavir (PaxlovidTM) - Oral Anti-viral Drugs in COVID-19: A Systematic Review

The COVID-19 pandemic situation demands the discovery of newer drugs and/ or repurposing of the existing drugs. The anti-viral drugs approved for COVID-19 are remdesivir and favipiravir. Two more directly acting oral anti-viral drugs have been granted Emergency Use Authorization by US-FDA, molnupiravir on December 23, 2021, and nirmatrelvir and ritonavir (PaxlovidTM) on December 22, 2021. Molnupiravir, an RNA-dependent RNA polymerase (RdRp) inhibitor, has also been approved in the UK and is under review with other regulatory agencies. PaxlovidTM (a combination of the new anti-viral drugs nirmatrelvir and ritonavir) has been developed and approved by US-FDA and CDSCO, India. Nirmatrelvir acts by inhibiting 3CL (chymotrypsin-like) protease enzyme and it is combined with ritonavir to slow down its breakdown by cytochrome P450 enzymes and to increase the bioavailability. Both molnupiravir and PaxlovidTM have been approved for mild and moderate COVID-19 and in patients who have a higher risk of disease progression to severe disease including hospitalisation and death. This article systematically reviews the clinical trials of molnupiravir and PaxlovidTM that evaluated their efficacy and safety against COVID-19 in both published and unpublished literature.

Abstract 290: Circulating FAS Is A Novel Serum-based Diagnostic Biomarker For PAD

A persistent challenge is the lack of reliable serum diagnostic tests for peripheral arterial disease (PAD). Serum cholesterol levels lack sensitivity for PAD and are not predictive of disease progression. Our team previously demonstrated that serum circulating Fatty Acid Synthase (cFAS) correlates with incidence of PAD and does not correlate with serum lipids. Therefore, we hypothesized that cFAS can be an independent diagnostic biomarker for PAD in a larger cohort, with or without diabetes. An IRB-approved consecutive (2014-2018) cohort was used to identify individuals with PAD/diabetes, as well as healthy controls. Consented patients provided a serum sample, and total cFAS content was measured with ELISA. Demographics and incidence of PAD/diabetes were collected from chart review. Serum cFAS and demographics were compared, and regression was used to determine correlations with cFAS. A total of 165 patients met inclusion criteria. Of these, 61 (37%) had PAD and diabetes (Group 1), 64 (38.8%) had PAD and no diabetes (Group 2), and 40 (24.2%) were healthy controls (Group 3). Compared to Group 3, Groups 1&amp;2 were significantly older, had more males, and higher incidence of cardiovascular co-morbidities (p&lt;0.001). Compared to Group 2, Group 1 had a higher incidence of cardiovascular/cerebrovascular disease, CHF, and HTN (p&lt;0.05). Despite these differences, both Groups 1&amp;2 had significantly higher serum cFAS content than Group 3 (p&lt;0.01 and p=0.01, respectively). In the whole cohort, there were significant correlations between cFAS and PAD severity and between cFAS and smoking status. (p=0.02, p=0.01 respectively). Our study suggests that cFAS can serve as an independent serum-based diagnostic biomarker for PAD, regardless of diabetes status. Future studies will further validate this serum biomarker and determine its predictive value for identifying individuals who are at highest risk of disease progression.

A modern day perspective on smoking in peripheral artery disease.

Peripheral artery disease (PAD) is associated with increased risk of cardiovascular morbidity and mortality, poor functional status, and lower quality of life. Cigarette smoking is a major preventable risk factor for PAD and is strongly associated with a higher risk of disease progression, worse post-procedural outcomes, and increased healthcare utilization. The arterial narrowing due to atherosclerotic lesions in PAD leads to decreased perfusion to the limbs and can ultimately cause arterial obstruction and limb ischemia. Endothelial cell dysfunction, oxidative stress, inflammation, and arterial stiffness are among the key events during the development of atherogenesis. In this review, we discuss the benefits of smoking cessation among patients with PAD and the use of smoking cessation methods including pharmacological treatment. Given that smoking cessation interventions remain underutilized, we highlight the importance of incorporating smoking cessation treatments as part of the medical management of patients with PAD. Regulatory approaches to reduce the uptake of tobacco product use and support smoking cessation have the potential to reduce the burden of PAD.

Facilitating oral COVID-19 therapy utilization through a pharmacy consult service

BackgroundTwo oral therapies, nirmatrelvir/ritonavir (Paxlovid) and molnupiravir (Lagevrio), are now available for the treatment of coronavirus disease 2019 (COVID-19). Treatment guidelines recommend using these agents for nonhospitalized adults with mild to moderate COVID-19 who are at high risk of disease progression. Despite guideline recommendations, therapy is frequently underutilized, resulting in lost opportunity to prevent severe outcomes including death. ObjectiveThis study aimed to describe the implementation of a pharmacy consult service for oral COVID-19 therapy within the ambulatory care setting. Practice descriptionUpon receipt of a positive COVID-19 test result, providers were encouraged to place a pharmacy consult for review. Information required within the consult submission served as a simple guide for determining eligibility for therapy. Once submitted, the pharmacist would identify which oral COVID-19 medication and dosage was most appropriate. In addition, for nirmatrelvir/ritonavir, the pharmacist would provide clear and concise instructions on how to manage any significant drug-drug interactions identified. Upon consult completion, the provider would order the appropriate therapy. Practice innovationWe depict an interdisciplinary approach to facilitate oral COVID-19 therapy utilization at a health care system level. EvaluationVeterans with a positive COVID-19 test from January 10, 2022, to July 10, 2022, were identified. A chart review was then used to collect relevant patient demographics and outcomes. The primary outcome was the eligibility for and subsequent prescribing of oral COVID-19 therapy. ResultsOf the 245 positive COVID-19 cases, 172 (70%) were eligible for oral COVID-19 therapy. Of those eligible, 118 (68.6%) were offered therapy and 95 (80.5%) accepted. Nirmatrelvir/ritonavir was the predominant agent used with 16% requiring renal dosage adjustment. Pharmacists identified 167 significant drug-drug interactions with nirmatrelvir/ritonavir encompassing 42 unique medications. Fourteen of the interactions warranted the utilization of molnupiravir. ConclusionThe utilization of a pharmacy consult service has facilitated interdisciplinary team collaboration and ultimately empowered the utilization of oral COVID-19 therapy.

Use of monoclonal antibody therapy in hematologic patients with mild‐to‐moderate COVID‐19: A retrospective single‐center experience

In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n= 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n= 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n= 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n= 0/26 and 36% n= 4/11, respectively; p< 0.01). This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients.

Abstract 5400: Predicting disease progression in inoperable localized NSCLC patients using cfDNA fragmentomics assay

Abstract Background: There is an urgent clinical need to accurately predict the risk for disease progression in post-treatment NSCLC patients. However, the current ctDNA mutation profiling approaches were limited by low sensitivity, while the cfDNA fragmentomics profiling has shown an excellent capability for cancer early detection in NSCLC and therefore exhibits great potential for predicting disease progression. In this retrospective study, we aim to develop a non-invasive liquid biopsy assay utilizing cfDNA fragmentomics profiling for predicting disease progression in inoperable localized NSCLC patients. Methods: The study cohort retrospectively enrolled 44 patients diagnosed with inoperable localized NSCLC who received first-line chemoradiotherapy/radiotherapy (including 23 disease progression during follow-up). Plasma samples were collected during or post-treatments, including 39 at the fourth week of treatment (TP1), 33 and 25 at 1 (TP2) and 3 (TP3) months post-treatment, respectively. cfDNA fragmentomic profiling, generated based on target sequencing data, was used to fit Regularized Cox Regression models. For each time point, a leave-one-out cross-validation (LOOCV) was performed to evaluate the models’ predictive performances, which was subsequently compared against the ctDNA status determined by the mutation-based method. Results: Our cfDNA fragmentomics assay showed excellent performance detecting patients with a high risk for disease progression. At TP1, the high-risk patients detected by our model showed an increased risk of 3.62 times (hazard ratio [HR] = 3.62, p = 0.0026) for disease progression, compared to 3.91 times (HR = 3.91, p = 0.0022) and 4.00 times (HR = 4.00, p = 0.019) for TP2 and TP3, respectively. These fragmentomics determined HRs were higher compared to the ctDNA mutation-based results (HR = 2.08, p = 0.074; HR = 1.49, p = 0.61) at TP1 and TP3, albeit being lower at TP2 (HR = 9.47, p &amp;lt; 0.0001). At TP1, the predictive model reached 40% sensitivity at 92.9% specificity, which was higher than the mutation-based method (40% sensitivity at 78.6% specificity), while the combination of the two methods reached a higher sensitivity (60%). Finally, a subset of the cohort (N = 19) with data for all three time points (TP1, TP2 and TP3) was examined, and the patients were labelled as high-risk for having a positive prediction or ctDNA status at any time point. The combined methods could predict disease progression with an excellent sensitivity of 88.9% at 80% specificity. Conclusions: We developed a cfDNA fragmentomics assay for predicting disease progression in inoperable NSCLC patients. This assay showed increased predicting power during and post treatment compared to the ctDNA mutation-based method, thus illustrating a great clinical potential to guide treatment decisions in inoperable NSCLC patients. Citation Format: Yin Yang, Tao Zhang, Jingbo Wang, Jianyang Wang, Wanxiangfu Tang, Hua Bao, Haimeng Tang, Xue Wu, Yang Shao, Xin Wang, Yuqi Wu, Linfang Wu, Xin Xu, Kunpeng Xu, Jingjing Zhao, Luhua Wang, Nan Bi. Predicting disease progression in inoperable localized NSCLC patients using cfDNA fragmentomics assay. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5400.

PD07-09 MANAGEMENT AND OUTCOMES OF MEDICALLY IMMUNOSUPPRESSED PATIENTS WITH CT1 RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023PD07-09 MANAGEMENT AND OUTCOMES OF MEDICALLY IMMUNOSUPPRESSED PATIENTS WITH CT1 RENAL CELL CARCINOMA Ali Ghasemzadeh, Eric Wendt, Brendan Dolan, Juliana Craig, Kyle Richards, Tudor Borza, Glenn Allen, David Jarrard, E. Jason Abel, and Daniel Shapiro Ali GhasemzadehAli Ghasemzadeh More articles by this author , Eric WendtEric Wendt More articles by this author , Brendan DolanBrendan Dolan More articles by this author , Juliana CraigJuliana Craig More articles by this author , Kyle RichardsKyle Richards More articles by this author , Tudor BorzaTudor Borza More articles by this author , Glenn AllenGlenn Allen More articles by this author , David JarrardDavid Jarrard More articles by this author , E. Jason AbelE. Jason Abel More articles by this author , and Daniel ShapiroDaniel Shapiro More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003231.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although there is a paucity of data, non-metastatic small renal cell carcinoma (RCC) patients who are medically immunosuppressed because of a prior organ transplant or treatment of an underlying disease have a theoretically higher risk of disease progression. This study describes the treatment and outcomes of medically immunosuppressed patients with clinical T1 RCC (cT1). METHODS: An institutional database of patients treated or biopsied for RCC was queried for patients with pathologic diagnosis of cT1 RCC and were on chronic medical immunosuppression, defined as use of a WHO designated immunosuppressant or prednisone ≥5mg for at least 3 months prior to treatment of RCC and continued use during follow up. Outcomes for patients undergoing 1) surgery 2) ablation or 3) active surveillance (AS) are described. Wilcoxon Rank Sum, Fisher’s exact test and Kaplan Meier analysis was performed. RESULTS: Between 2010-2022, 74 medically immunosuppressed patients with RCC were identified who were treated with surgery (n=29), ablation (n=33), or AS (n=12). Median age was 60 years (IQR 51-68), median Charlson comorbidity index was 3 [IQR 2-5] and median follow-up was 48 months (IQR 29-80). Most patients were immunosuppressed due to prior organ transplant (57/74, 77%). Seven (58%) AS patients underwent deferred treatment (6 ablations, 1 nephrectomy) due to progressive tumor growth. Surgical patients were significantly younger than ablation or AS patients and had fewer comorbidities. The surgery and ablation 30-day readmission rate (17% vs 9%, p=0.7) and 90-day complication rate (24% vs 21%, p=0.9) was similar, respectively. No 90-day deaths occurred. One (3%) surgical and 2 (6%) ablation patients recurred locally. One (3%) surgical, 1 (3%) ablation, and no AS patients progressed to metastatic disease. No significant differences were noted for the local recurrence free, metastasis free, and overall survival for the 3 cohorts (P>0.05 for all) (Figure 1). CONCLUSIONS: For medically immunosuppressed patients with cT1 RCC, treatment outcomes are similar to historical series of non-immunosuppressed patients. These data suggest that small RCC tumors are not more aggressive in patients with medical immunosuppression but require careful selection to avoid morbidity and maintain oncologic control. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e165 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ali Ghasemzadeh More articles by this author Eric Wendt More articles by this author Brendan Dolan More articles by this author Juliana Craig More articles by this author Kyle Richards More articles by this author Tudor Borza More articles by this author Glenn Allen More articles by this author David Jarrard More articles by this author E. Jason Abel More articles by this author Daniel Shapiro More articles by this author Expand All Advertisement PDF downloadLoading ...

A metabolomics approach to the validation of predictive metabolites and phenotypic expression in non-alcoholic fatty liver disease

AimsNonalcoholic fatty liver disease (NAFLD) is becoming more common and severe. Individuals with NAFLD have an altered composition of gut- microbial metabolites. We used metabolomics profiling to identify microbial metabolites that could indicate gut-liver metabolic severity. Noninvasive biomarkers are required for NAFLD, especially for patients at high risk of disease progression. Main methodsWe compared the stool metabolomes, untargeted metabolomics, and clinical data of 80 patients. Patients with nonalcoholic fatty liver (NAFL: n = 16), nonalcoholic steatohepatitis (NASH: n = 26), and cirrhosis (n = 19) and healthy control individuals (HC: n = 19) were enrolled. The identified metabolites in NAFLD were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Gas chromatography–mass spectrometry (GC–MS) and liquid chromatography coupled to time-of-flight–mass spectrometry (LC–TOF-MS) were used to analyze metabolites. Key findingsUntargeted metabolomics was used to identify and quantify 103 metabolites. Principal component analysis (PCA) was used to assess the metabolic discrimination of NAFL, NASH, and cirrhosis. Short-chain fatty acids (SCFA) levels were significantly lower in NAFLD patients, including those of acetate (p = 0.03), butyrate (p = 0.0008), and propionate. The stool cholic acid (p = 0.001) level was significantly increased in NAFLD patients. Palmitoylcarnitine and l-carnitine levels were significantly increased in NASH and cirrhosis patients. The phenotypic expression of these metabolites was linked to β-oxidation. SignificanceWe demonstrated a distinct metabolome profile in NAFLD patients with NAFL, NASH, and cirrhosis. We also discovered that the expression of certain metabolites and metabolic pathways was linked to NAFLD.

Real-World Experience of the Comparative Effectiveness and Safety of Molnupiravir and Nirmatrelvir/Ritonavir in High-Risk Patients with COVID-19 in a Community Setting.

Molnupiravir (MOV) and nirmatrelvir/ritonavir (NMV/r) are efficacious oral antiviral agents for patients with the 2019 coronavirus (COVID-19). However, little is known about their effectiveness in older adults and those at high risk of disease progression. This retrospective single-center observational study assessed and compared the outcomes of COVID-19 treated with MOV and NMV/r in a real-world community setting. We included patients with confirmed COVID-19 combined with one or more risk factors for disease progression from June to October 2022. Of 283 patients, 79.9% received MOV and 20.1% NMV/r. The mean patient age was 71.7 years, 56.5% were men, and 71.7% had received ≥3 doses of vaccine. COVID-19-related hospitalization (2.8% and 3.5%, respectively; p = 0.978) or death (0.4% and 3.5%, respectively; p = 0.104) did not differ significantly between the MOV and NMV/r groups. The incidence of adverse events was 2.7% and 5.3%, and the incidence of treatment discontinuation was 2.7% and 5.3% in the MOV and NMV/r groups, respectively. The real-world effectiveness of MOV and NMV/r was similar among older adults and those at high risk of disease progression. The incidence of hospitalization or death was low.

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

First-line Chemotherapy Response Is Associated With Clinical Outcome During Immune Checkpoint Inhibitor Treatment in Advanced Urothelial Carcinoma: A Real World Retrospective Study.

Immune checkpoint inhibitors (ICI) have become important tools for the treatment of advanced urothelial carcinoma (aUC). However, the clinical strategy using ICIs and chemotherapy is still controversial. The aim of this study was to evaluate the association of clinical parameters in aUC patients with ICI treatment. We retrospectively analyzed aUC patients who received atezolizumab and pembrolizumab between January 2015 and October 2020. The associations between baseline demographics and clinical outcomes were evaluated. Of the 74 included patients, the median age was 67 years. Among them, 53 patients received atezolizumab and 21 received pembrolizumab. There were 50 patients receiving first line ICIs therapy and 24 receiving second line monotherapy. Fifty-two (83.87%, 52/62) received cisplatin among all chemotherapy patients. The median progression free survival was 10.94 months, and the overall survival was 28.44 months. Poor chemotherapy response or no chemotherapy, liver metastases, Eastern Cooperative Oncology Group (ECOG) status and higher neutrophil/lymphocyte ratio (NLR) were associated with higher risk of disease progression (HR=5.70, 95% CI=2.04-15.90, p=0.001; HR=6.08, 95% CI=1.79-20.57, p=0.004; HR=5.40, 95% CI=1.76-16.57, p=0.003; HR=6.08, 95% CI=2.56-14.44, p<0.001 and HR=1.02, 95% CI=1.01-1.03, p=0.002, respectively). Liver metastases and WBC before ICI were associated with increased risk of death (HR=11.95, 95% CI=3.22-44.34, p<0.001; HR=1.0001, 95%=CI=1.00001-1.00002, p=0.036 respectively) while ICI response was associated with decreased death (HR=0.22, 95%CI=0.08-0.62, p=0.004). Chemotherapy response was associated with better ICI treatment response (OR=6.52, 95% CI=1.45-29.24, p=0.014) while lymph node metastases and poor ECOG status were associated with poor ICI response (OR=0.31, 95% CI=0.10-0.94, p=0.038; OR=0.32, 95% CI=0.11-0.95, p=0.040). Our real-world data show a predictive role of first-line chemotherapy response to ICI treatment efficacy in aUC patients as well as other prognostic factors, such as ECOG status, serum WBC or NLR and liver metastases.

MRI-AST (MAST) Score Accurately Predicts Major Adverse Liver Outcome, Hepatocellular Carcinoma, Liver Transplant, and Liver-Related Death

The MRI-AST (MAST) score accurately identifies patients with at-risk nonalcoholic steatohepatitis, defined as nonalcoholic steatohepatitis with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2 at highest risk for disease progression. It is important to determine the robustness of the MAST score in predicting major adverse liver outcomes (MALO), hepatocellular carcinoma (HCC), liver transplant, and death. This retrospective analysis included patients with nonalcoholic fatty liver disease from a tertiary care center who underwent magnetic resonance imaging proton density fat fraction, magnetic resonance elastography, and laboratory testing within 6 months from 2013 to 2022. Other causes of chronic liver disease were excluded. Hazard ratios between logit MAST and MALO (ascites, hepatic encephalopathy, or bleeding esophageal varices), liver transplant, HCC, or liver-related death were computed using a Cox proportional hazards regression model. We computed the hazard ratio of MALO or death associated with MAST scores 0.165-0.242 and 0.242-1.000, using MAST scores 0.000-0.165 as the reference group. Among 346 total patients, average age was 58.8 years with 52.9% females and 34.4% with type 2 diabetes. Average alanine aminotransferase was 50.7 IU/L (24.3-60.0 IU/L), aspartate aminotransferase was 38.05 IU/L (22.00-41.00 IU/L), platelets were 242.9× 109/L (193.8-290.0× 109/L), proton density fat fraction was 12.90% (5.90%-18.22%), and liver stiffness on magnetic resonance elastography was 2.75 kPa (2.07-2.90 kPa). Median follow-up was 29.5 months. Fourteen had adverse outcomes, including 10 MALO, 1 HCC, 1 liver transplant, and 2 liver-related deaths. The Cox regression of MAST versus adverse event rate had a hazard ratio of 2.01 (95% confidence interval, 1.59-2.54; P < .0001) for each 1 logit unit increases in MAST. The corresponding Harrell concordance statistic (C statistic) was 0.919 (95% confidence interval, 0.865-0.953). The MAST score ranges of 0.165-0.242 and 0.242-1.0, respectively, had adverse event rate hazard ratio of 7.75 (1.40-42.9; P= .0189) and 22.11 (6.59-74.2; P < .0000) relative to MAST 0-0.165. The MAST score noninvasively identifies at-risk nonalcoholic steatohepatitis and accurately predicts MALO, HCC, liver transplant, and liver-related death.

Prognosis and histology of sporadic synchronous and metachronous meningiomas and comparative analyses with singular lesions

Synchronous or metachronous growth of multiple tumors (≥ 2) is found in up to 20% of meningioma patients. However, biological as well as histological features and prognosis are largely unexplored. Clinical and histological characteristics were retrospectively investigated in 95 patients harboring 226 multiple meningiomas (MMs) and compared with 135 cases of singular meningiomas (SM) using uni- and multivariate analyses. In MM, tumors occurred synchronously and metachronously in 62% and 38%, respectively. WHO grade was intra-individually constant in all but two MMs, and histological subtype varied in 13% of grade 1 tumors. MM occurred more commonly in convexity/parasagittal locations, while SM were more frequent at the skull base (p < .001). In univariate analyses, gross total resection (p = .014) and high-grade histology in MM were associated with a prolonged time to progression (p < .001). Most clinical characteristics and rates of high-grade histology were similar in both groups (p ≥ .05, each). Multivariate analyses showed synchronous/metachronous meningioma growth (HR 4.50, 95% CI 2.26–8.96; p < .001) as an independent predictor for progression. Compared to SM, risk of progression was similar in cases with two (HR 1.56, 95% CI .76–3.19; p = .224), but exponentially raised in patients with 3–4 (HR 3.25, 1.22–1.62; p = .018) and ≥ 5 tumors (HR 13.80, 4.06–46.96; p < .001). Clinical and histological characteristics and risk factors for progression do not relevantly differ between SM and MM. Although largely constant, histology and WHO grade occasionally intra-individually vary in MM. A distinctly higher risk of disease progression in MM as compared to SM might reflect different underlying molecular alterations.

Carotid Artery Disease in the Era of Biomarkers: A Pilot Study

The intima-media thickness (IMT) and its irregularities or ulcerations in the common carotid artery (CCA) are useful tools as sentinel biomarkers for the integrity of the cardiovascular system. Total homocysteine and lipoprotein levels are the most commonly used elements in cardiovascular risk stratification. Duplex ultrasound (DUS), associated with serum biomarkers, can be used simply to assess the degree of atherosclerotic disease and cardiovascular risk. This study highlights the role of different kinds of biomarkers, showing their usefulness and potentiality in multi-district atherosclerotic patients, especially for early diagnosis and therapy effectiveness monitoring. A retrospective analysis performed from September 2021 to August 2022, of patients with carotid artery disease, was performed. A total of 341 patients with a mean age of 53.8 years were included in the study. The outcomes showed an increased risk of stroke in patients with significative carotid artery disease, nonresponsive to therapy, monitored through a series of serum biomarkers (homocysteine, C-reactive protein, and oxidized LDL). In this reported experience, the systematic use of DUS in association with the multiple biomarkers approach was effective for the early identification of patients at higher risk of disease progression or inefficient therapy.