Citations

Abstract Background: Oncogenic alterations (gene amplification, mutation, and fusion/rearrangements) of fibroblast growth factor receptor 2 (FGFR2) are rare and occur at varying frequencies across solid tumor types and have become critical therapeutic targets in drug development. First generation FGFR pan-kinase inhibitors non-selectively inhibit FGFR1-4 and are associated with dose limiting toxicities and narrow therapeutic windows. Off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) and on-target acquired resistance have led to limited efficacy, which is primarily seen in FGFR2-fusion+ intrahepatic cholangiocarcinoma. Therapies that selectively target FGFR2 remain an unmet need in advanced breast cancer as well as other solid tumor types. RLY-4008 is a novel, oral FGFR2 inhibitor designed to overcome the limitations of pan-FGFR inhibitors (FGFRi) by potently and selectively targeting primary oncogenic FGFR2 alterations and acquired resistance mutations. RLY-4008 is > 200-fold selective over FGFR1, > 80- and > 5000-fold selective over FGFR3 and FGFR4 respectively. Here we describe a phase 1/2 study to investigate the safety and antitumor activity in advanced FGFR2 altered cancers, including breast cancer. Methods: ReFocus is a phase 1/2 open label global study evaluating the safety and efficacy of RLY-4008 (NCT04526106) in adult patients with advanced unresectable and/or metastatic cancers harboring an FGFR2 alteration. Key eligibility criteria include: documented FGFR2 alteration in blood or tissue per local assessment, ECOG performance status of 0-1, disease that is refractory or not adequately responding to standard therapy, has no available standard therapy, or patient is intolerant of, or declined standard therapy (including pan-FGFRi), and measurable or evaluable disease per RECIST 1.1. FGFR2 alteration will be confirmed retrospectively by central laboratory assessment. Part 1 dose escalation employed the Bayesian Optimal Interval (BOIN) design to determine the MTD/RP2D of RLY-4008. Part 2 dose expansion is presently enrolling patients at the RP2D of RLY-4008 and includes 5 cohorts comprised of patients with: 1. FGFR2 fusion+ cholangiocarcinoma previously treated with an FGFRi; 2. FGFR2 fusion+ cholangiocarcinoma not previously treated with an FGFRi; 3. FGFR2 fusion+ solid tumors; 4. FGFR2 mutation+ solid tumors and 5. FGFR2 amplified solid tumors. Solid tumors in cohorts 3, 4 and 5 will have a focus in breast cancer. The primary endpoint is objective response rate (ORR); key secondary endpoints include: duration of response, safety and tolerability, correlation of FGFR2 genotype by central tissue assessment with antitumor response, characterization of PK profile, and quality of life. US enrollment began September 2020 and has expanded into Europe and Asia. Clinical trial information: NCT04526106. Citation Format: Suneel Kamath, David Tai, Irene Moreno, Hani Babiker, Zhaohui Jin, Changhoon Yoo, Fabien Ricard, Kai Yu Jen, Jim Coward, Jia Liu, Frans Opdam, Michael Millward, Mariano Ponz-Sarvise, Jeffrey Yachnin, Richard Kim, Joon Oh Park, Vivek Subbiah, Alison M. Schram. ReFocus: A Phase 1/2 Study of the Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients with Advanced Solid Tumors Including Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-24-01.

Background: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction. Purpose: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient’s outcome at 6-year follow-up. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx Activity Rating Scale. Patients were followed up at 6 years and asked to complete the identical set of outcome instruments. Regression analysis assessed the meniscal and articular cartilage pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction. Results: An overall 1234 patients were enrolled (716 males, 58%; median age, 26 years). Surgeons reported the pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (43%), lateral femoral condyle (29%), medial tibial plateau (11%), lateral tibial plateau (17%), patella (30%), and trochlea (21%). Six-year follow-up was obtained on 79% of the sample (980/1234). Meniscal pathology and articular cartilage pathology (medial femoral condyle, lateral femoral condyle, lateral tibial plateau, trochlea, and patella) were significant drivers of poorer patient-reported outcomes at 6 years (IKDC, KOOS, WOMAC, and Marx). The most consistent factors driving outcomes were having a medial meniscal excision (either before or at the time of revision surgery) and patellofemoral articular cartilage pathology. Six-year Marx activity levels were negatively affected by having either a repair/excision of the medial meniscus (odds ratio range, 1.45-1.72; P≤ .04) or grade 3-4 patellar chondrosis (odds ratio, 1.72; P = .04). Meniscal pathology occurring before the index revision surgery negatively affected scores on all KOOS subscales except for sports/recreation ( P < .05). Articular cartilage pathology significantly impaired all KOOS subscale scores ( P < .05). Lower baseline outcome scores, higher body mass index, being a smoker, and incurring subsequent surgery all significantly increased the odds of reporting poorer clinical outcomes at 6 years. Conclusion: Meniscal and chondral pathology at the time of revision ACL reconstruction has continued significant detrimental effects on patient-reported outcomes at 6 years after revision surgery.

Background: App-based technologies could enhance patient and caregiver communication and provide alerts that potentially reducing readmissions. However, the burden of App alerts needs to be optimized to reduce provider burnout. Aim: The purpose of this study was to determine subjective and objective burden of using the Patient Buddy App, a health information technology (HIT) on providers in a randomized multicenter trial, who completed a semi-quantitative Likert scale survey regarding training procedures, data and privacy concerns, follow-up details, and technical support. This randomized multicenter trial recruits cirrhosis inpatients and their caregivers, and randomizes them into standard-of-care, HIT (communication only via App) and HIT+visits (App+phone calls/visits) for 30 days after discharge. The alerts are monitored by providers through a central iPad. The reason(s) and number of alerts were recorded as the objective burden. A total of 1442 messages were sent as alerts from the 103 dyads (patient + caregiver) (n=206) randomized to HIT arms. The most common messages related to Hepatic Encephalopathy (HE) (high or low bowel movement=50% or orientation tests=37%). Twelve providers completed the surveys reflecting the following themes—92% and 100%, felt adequately trained and confident about educating the patients and caregivers before roll out of App and had no concerns related to data and privacy; 70%, felt that appropriate time was spent on pursuing reason for data not being logged; 60% each, had issues with availability of adequate technical support and connectivity. Conclusion: The Patient Buddy App randomized multicenter trial till date shows an overall favorable rating regarding training procedures/education, privacy concerns, and ease of message follow-up, from providers. However, it is important to gauge and address subjective and objective burdens of monitoring human resources in current and future HIT studies to avoid burnout and to ensure successful study completion.

Abstract Alcoholic hepatitis (AH) develops in a small percentage of heavy drinkers. The adaptive immune system of AH patients is hyper-activated, yet dysregulated and ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are found in liver, intestinal mucosa, and peripheral blood and contribute to protection against infectious diseases. To determine whether MAIT cells were dysregulated in heavy drinkers and the effect of alcohol abstinence on MAIT cell recovery, we compared peripheral MAIT cells between AH patients and heavy drinkers without liver disease (HDC) at baseline and 6- and 12-month followup. At baseline, AH patients had severely reduced frequency of MAIT cells than HDC and healthy donor controls (HC), whereas MAIT cell frequency was not significantly different between HDC and HC. In addition, MAIT cells in AH patients expressed higher levels of the activation markers (CD69, CD38, and HLA-DR) as well as the immune checkpoint inhibitor PD-1. Multiplex immunoassays showed that plasma levels of several cytokines related to MAIT cell activation were elevated in AH patients (IFN-s, IL-7, IL-15, IL-17, IL-18, and IL-23, and TNF-a). In AH patients, the frequency MAIT cells and CD38-expressing MAIT cells correlated with levels of several cytokines and AST. At followup, AH patients had increased MAIT cell frequency and decreased MAIT cell activation with cessation of alcohol. However, abstinent AH patients still had higher levels of CD38-expressing MAIT cells than HDC at 6-month followup. Conclusion Blood MAIT cells were severely reduced and were dysregulated in AH patients and alcohol abstinence partially reversed abnormalities in MAIT cell frequency and phenotype.

Objectives Fontan-associated liver disease (FALD) is universal post-Fontan palliation; however, its impact on survival remains controversial and current diagnostic tools have limitations. We aimed to assess the prognostic role of liver fibrosis scores (aminotransferase to platelet ratio [APRI] and fibrosis-4 [FIB-4]) and their association with haemodynamics and other markers of liver disease. Methods 159 adults (age ≥18 years) post-Fontan undergoing catheterisation at Mayo Clinic, Minnesota, between 1999 and 2017 were included. Invasive haemodynamics and FALD-related laboratory, imaging and pathology data were documented. Results Mean age was 31.5±9.3 years, while median age at Fontan procedure was 7.5 years (4–14). Median APRI score (n=159) was 0.49 (0.33–0.61) and median FIB-4 score (n=94) was 1.12 (0.71–1.65). Correlations between APRI and FIB-4 scores and Fontan pressures (r=0.30, p=0.0002; r=0.34, p=0.0008, respectively) and pulmonary arterial wedge pressure (r=0.25, p=0.002; r=0.30, p=0.005, respectively) were weak. Median average hepatic stiffness by magnetic resonance elastography was 4.9 kPa (4.3–6.0; n=26) and 24 (77.4%) showed stage 3 or 4 liver fibrosis on biopsy; these variables were not associated with APRI/FIB-4 scores. On multivariable analyses, APRI and FIB-4 scores were independently associated with overall mortality (HR 1.31 [1.07–1.55] per unit increase, p=0.003; HR 2.15 [1.31–3.54] per unit increase, p=0.003, respectively). Conclusions APRI and FIB-4 scores were associated with long-term all-cause mortality in Fontan patients independent of other prognostic markers. Correlations between haemodynamic status and liver scores were weak; furthermore, most markers of liver fibrosis failed to correlate with non-invasive indices, underscoring the complexity of FALD.

INTRODUCTION: The triglyceride (TG) threshold for diagnosis of chylous ascites in patients with portal hypertension remains uncertain. METHODS: Retrospective analysis of lipoprotein electrophoresis was conducted in 286 consecutive ascites samples. RESULTS: Ascitic TG ≥ 81 mg/dL is 95.4% sensitive and 94.6% specific for chylous ascites diagnosed by the presence of significant chylomicron population. DISCUSSION: The cutoff for chylous ascites diagnosis should be TG ≥ 81 mg/dL.

Nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases are both highly prevalent conditions around the world, and emerging data have shown an association between them. This review found several longitudinal and cross-sectional studies showing that NAFLD was associated with coronary artery disease, cardiac remodeling, aortic valve remodeling, mitral annulus valve calcifications, diabetic cardiomyopathy, diastolic cardiac dysfunction, arrhythmias, and stroke. Although the specific underlying mechanisms are not clear, many hypotheses have been suggested, including that metabolic syndrome might act as an upstream metabolic defect, leading to end-organ manifestations in both the heart and liver. Management of NAFLD includes weight loss through lifestyle interventions or bariatric surgery, and pharmacological interventions, often targeting comorbidities. Although there are no Food and Drug Administration–approved nonalcoholic steatohepatitis-specific therapies, several drug candidates have demonstrated effect in the improvement in fibrosis or nonalcoholic steatohepatitis resolution. Further studies are needed to assess the effect of those interventions on cardiovascular outcomes, the major cause of mortality in patients with NAFLD. In conclusion, a more comprehensive, multidisciplinary approach to diagnosis and management of patients with NAFLD and cardiovascular diseases is needed to optimize clinical outcomes.