Nayfeh, Tarek

Abstract Background and Aim Following the approval of the first agent for the management of metabolic dysfunction‐associated steatohepatitis (MASH), identification of patients with fibrotic MASH (MASH with NAS ≥ 4 and fibrosis stage ≥ 2) is crucial. We assessed the performance of FibroScan‐aspartate aminotransferase (AST) score (FAST) for ruling in/out fibrotic MASH. Methods We searched Medline, Cochrane Library, Web of Science, Scopus, and gray literature sources up to January 11, 2024. Studies were eligible if they assessed the accuracy of FAST score for the detection of fibrotic MASH using biopsy as the reference standard at previously reported thresholds (FAST ≥ 0.67 for ruling‐in and ≤ 0.35 for ruling‐out fibrotic MASH). We calculated pooled sensitivity and specificity estimates for FAST thresholds alongside 95% confidence intervals following bivariate random‐ effects models. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Results We included 16 studies with 8838 participants. A FAST score ≥ 0.67 yielded a pooled specificity of 0.87 (0.82–0.90) while a FAST score ≤ 0.35 yielded a summary sensitivity of 0.88 (0.83–0.91). At a prevalence of 30%, the positive predictive value for ruling‐in fibrotic MASH was 60% while the negative predictive value for ruling‐out the target condition was 91%. AST levels, cirrhosis prevalence, and number of pathologists reviewing biopsies were sources of heterogeneity among studies. The certainty of evidence was low to very low. Conclusions FAST score can be used as a triage test for ruling out fibrotic MASH. Nevertheless, its low positive predictive value necessitates sequential testing for ruling‐in fibrotic MASH.

Abstract Context Low vitamin D status is common and is associated with various common medical conditions. Objective To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. Methods We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. Results Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D. Conclusion The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals’ and providers’ values and preferences and other important decisional and contextual factors to develop clinical recommendations.

Abstract Background: Recent advancements in novel therapeutics have resulted in improved survival over the last decade for patients with metastatic breast cancer, but there remain subsets of patients who experience disproportionately poor outcomes. Patients with visceral crisis (VC), defined by the 5th ESO ESMO as the presence of visceral metastasis with severe organ compromise and/or rapid progression, are often excluded from clinical trials of novel therapeutics. This is despite patients with VC having poorer clinical outcomes and a lack of guidelines consensus on best therapeutic practices. Thus, we sought to better characterize this patient cohort via a meta-analysis to elucidate clinical characteristics and treatment options. Methods: We searched MEDLINE, Embase, Cochrane, Scopus and other sources, from each database's inception to March 2023. The search strategy was designed and conducted by an experienced librarian with input from the study's principal investigator. Controlled vocabulary supplemented with keywords was used to search for patients with breast cancer in visceral crisis. Outcomes of interest included mortality and progression at different time points. Meta-analysis was conducted using the random-effects model. Results: The studies matching our initial inquiry was 154. After evaluation for patient number, and VC related outcomes, 16 studies (12 abstract only) met initial criteria. After data extraction, 12 studies were excluded due to insufficient outcomes delineated by VC. The treatment period was 01/2008 until 01/2022. The mean age at diagnosis of VC was 53.9 with a total of 6404 patients, 6259 were hormone positive, 41 Her2 positive and 87 triple negative. The type of VC included 212 liver dysfunction, 84 respiratory dysfunction, 40 with bone marrow dysfunction, 4 with SVC syndrome, and 43 with meningeal disease (VC type is not reported in every study). The treatments were varied and included multiple platinum doublets, CDK4/6 with endocrine therapy, platinum with bevacizumab, endocrine monotherapy and Her-2 targeted agents. Unfortunately, the number of patients per treatment group or VC type is not enough for targeted outcome analysis. The proportion of patients who progressed at 1, 6, 12 and 18 months were 0.17, 0.64, 0.95 and 0.91 respectively (2 studies Yang et al and Funasaka et al). Mortality assessed as proportion who expired at 1, 6, 12 and 18 months at 0.07, 0.44, 0.64 and 0.77 respectively (3 studies Yang et al, Funasaka et al and Franzoi et al) and at 24 months 0.89 in 4 studies (Yang et al, Funasaka et al, Dawood et al and Franzoi et al) (Table 1). Conclusions In this systematic review, we clearly demonstrate a lack of clinical trial data available to demonstrate specific outcomes based on chemotherapy, visceral crisis type or targeted treatment. The prognosis, however, is consistently poor with mortality at 64 percent by 12 months. Thus, further studies are needed to guide best treatment strategies that address both the poor clinical outcomes and therapeutic toxicities for patients with VC. Clinical trial groups and regulatory bodies overseeing new drug development for breast cancer should consider specific arms for patients with VC, instead of targeted exclusion from trials, as this strategy has proven effective in expansion of therapeutics for other challenging breast cancer subtypes. Table 1 Table 1: Proportion of progression and mortality. Progression studies include Yang et al 2022, Funasaka et al 2021. Mortality studies at 1, 6 and 12 months Yang et al 2022, Funasaka et al 2021 and Franzoi et al 2021. Mortality studies at 24 months Yang et al 2022, Funasaka et al 2021, Franzoi et al 2021, Dawood et al 2021. Citation Format: Michael Auster, Raed Benkhadra, Sophia Lee, Tamarah Aldawoodi, Larry Prokop, Tarek Nayfeh, Paromita Datta, Kate Lathrop. Meta-Analysis of Clinical Characteristics and Outcomes in Breast Cancer Patients with Visceral Crisis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-03.

SummaryBackground & AimsThe natural progression of hepatic decompensation in metabolic dysfunction‐associated steatotic liver disease (MASLD) is not well‐characterised. We aimed to describe it by conducting a retrospective analysis.MethodsThis longitudinal, retrospective analysis of well‐characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver‐related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured.ResultsOf the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow‐up of 3.2 years. Ascites was the most common first liver‐related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver‐related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy‐three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years.ConclusionThe most common first liver‐related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years.

Background and Aims: Transient elastography (TE), shear wave elastography, and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F). Approach and Results: A comprehensive search for studies assessing LSM by TE, shear wave elastography, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), using histopathology as the standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV coinfection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults. Conclusions: LSM from TE, shear wave elastography, and MRE shows acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Background and Aims: Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. Approach and Results: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR−) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66–6.25 and 0.23–0.80, 1.89–5.24 and 0.12–0.64, and 1.32–7.15 and 0.15–0.86, respectively; LR+ and LR− for NAFLD F2-4, F3-4, and F4 were 2.65–3.37 and 0.37–0.39, 2.25–6.76 and 0.07–0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. Conclusions: Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.

Background and Aims: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. HVPG, a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and availability, noninvasive liver disease assessments to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. Approach and Results: We conducted a systematic review of Ovid MEDLINE(R) Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database’s inception to April 22, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies, which compared noninvasive tests (blood and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥ 10 mm Hg) in patients with chronic liver disease. Outcomes included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. Nine studies with 2492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood-based tests, including aspartate-to-platelet ratio index (APRI) (56% sensitivity and 68% specificity) and FIB-4 (54% sensitivity and 73% specificity) had low accuracy measures. Imaging-based tests (transient elastography and shear wave elastography detection of liver stiffness measurement [LSM]) had better accuracy but also had substantial variation; at 15 kPa, TE sensitivity was 90%–96% and specificity was 48%–50%, while at 25 kPa, its sensitivity and specificity were 57%–85% and 82%–93%, respectively. The narrative review suggested that imaging-based tests are the best available noninvasive liver disease assessment to detect CSPH; CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. Conclusions: While imaging-based noninvasive liver disease assessment appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the systematic review. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

Introduction: Data on clinical outcomes of percutaneous closure of iatrogenic atrial septal defect (PC-ASD) in patients undergoing transcatheter edge-to-edge repair (TEER) or mitral valve replacement (TMVR) remains limited. We used a real-world USA database to evaluate the differences in the in-hospital outcomes between both groups. Hypothesis: Is there a clinical significance for PC-ASD in patients undergoing TEER or TMVR? Methods: We used the National Inpatient Sample (2015-2020) by utilizing ICD-10 codes to identify all patients who underwent TEER or TMVR with or without PC-ASD. Multivariate logistic regression was used for adjusted outcomes (adjusted odds ratio [aOR]). Results: A total of 44,065 eligible weighted hospitalizations were included: 39,625 (89.9%) of the patients underwent TEER and 4,440 (10.1%) underwent TMVR. Rates of PC-ASD were higher in TMVR group compared to TEER group (10.7% vs. 2.0%, p<0.01). In patients who underwent TEER without PC-ASD, PC-ASD was more associated with acute heart failure (AHF) (aOR 1.42 [1.19-1.68], p<0.01) and longer hospitalizations (aOR 1.64 [1.41-1.89], p<0.01), without significant difference in inpatient mortality (aOR 0.97 [0.61-1.54], p<0.01), cardiogenic shock (aOR 1.13 [0.85-1.51], p=0.21), need for mechanical circulatory support (MCS) (aOR 0.98 [0.61-1.54], p=0.18), and stroke. Compared to patients who underwent TMVR without PC-ASD, PC-ASD was associated with higher inpatient morality (aOR 1.65 [1.13-2.4], p<0.01), need for MCS (aOR 1.91 [1.33-2.73], p<0.01) without significant difference in AHF (aOR 1.19 [0.94-1.51], p=0.18] and cardiogenic shock (aOR 0.83 [0.56-1.22], p=0.43). Remarkably, PC-ASD was less associated with stroke (aOR 0.27 [0.10-0.72], p<0.01). Conclusions: Rates of PC-ASD after TEER were lower than after TMVR and were associated with worse in-hospital mortality and need for MCS in TMVR but not in TEER. Also, PC-ASD was less associated with stroke after TMVR.