Citations

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in the United States and worldwide. HCC screening among patients at elevated risk is associated with improved early detection and overall survival, but current ultrasound-based screening strategies are challenged by low adherence and suboptimal sensitivity. Blood-based screening tests have the potential to enhance adherence and improve early-stage HCC detection if they can demonstrate favorable performance compared with ultrasound-based screening. Here we present the design and rationale for ALTUS (A lternative to Ultrasound), a prospective, longitudinal, multicenter study in the United States to investigate the performance of the multi-target HCC blood test (mt-HBT) for the detection of HCC in a screening population. Methods: Adults with liver cirrhosis or chronic hepatitis B infection will be enrolled to undergo standard-of-care screening imaging and concurrent blood collection for the mt-HBT. All participants will undergo contrast-enhanced CT or MRI imaging with central radiology LI-RADS assessment as the reference method to determine HCC status. Participants without an identified malignancy will undergo a second screening visit and blood collection, and longitudinal clinical and imaging data will be collected up to 18 months from enrollment. The primary study objectives are to demonstrate that the mt-HBT is non-inferior to ultrasound for early-stage HCC sensitivity and to assess mt-HBT HCC specificity. The secondary objective is to assess mt-HBT overall sensitivity. Results: ALTUS is in progress with readout of the primary analysis expected in 2025. Conclusions: This prospective head-to-head comparison of the mt-HBT versus ultrasound will provide novel data regarding the performance and utility of the mt-HBT for HCC screening.

Abstract A methodology was developed for potential determination of the material properties of inhomogeneous and anisotropic biomembranes. Mathematical estimations and computer simulations were performed to determine the effect of load and displacement errors on the property values. The results indicated that the material properties were particularly sensitive to displacement errors. The determination of non-dominant components requires more accurate experimental measurements.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Background and Aims: Primary biliary cholangitis is a chronic cholestatic liver disease that may progress to cirrhosis and liver failure. For patients with inadequate response or intolerance to ursodeoxycholic acid, peroxisome proliferator–activated receptor (PPAR) agonists have emerged as second-line options. This study assessed the comparative effectiveness and safety of PPAR agonists in primary biliary cholangitis through a systematic review and network meta-analysis. Approach and Results: A systematic review identified randomized controlled trials evaluating PPAR agonists versus ursodeoxycholic acid, with or without placebo. A frequentist network meta-analysis assessed biochemical response (primary outcome) and ALP normalization (secondary outcome). Pairwise meta-analyses were performed for percentage change in ALP and total bilirubin, and adverse events leading to treatment discontinuation. Data were stratified by baseline ALP, and a random-effects model was used. Eight randomized controlled trials (727 participants) evaluating 4 PPAR agonists were included. All agents outperformed placebo in achieving biochemical response and ALP normalization. Bezafibrate ranked highest for the primary outcome; both bezafibrate and seladelpar ranked highest for the secondary outcome. Percentage ALP reduction did not vary by baseline ALP. Total bilirubin changes were similar across arms, and treatment discontinuations due to adverse events were infrequent. Conclusions: PPAR agonists are effective second-line therapies for primary biliary cholangitis. Treatment ranking differences likely reflect variations in outcomes, populations, and drug mechanisms. In the absence of head-to-head trials, network meta-analysis provides important insights into comparative effectiveness. Further studies are warranted to confirm long-term safety and improve the evaluation of patient-centered outcomes.

Abstract Aims To assess the potential for artificial intelligence-enabled electrocardiogram (AI-ECG) to serve as a long-term cardiac surveillance tool and predict left ventricular systolic dysfunction in childhood cancer patients. Methods and results We assessed performance of our previously established AI-ECG model to predict left ventricular ejection fraction (LVEF) ≤50% and ≤40% in patients with childhood cancer during internal testing (Boston Children’s Hospital) and external validation (Children’s Hospital of Philadelphia). The internal test cohort comprised 447 patients [57% male; age at cancer diagnosis 11.2 (5.4–15.7) years; 1553 ECG–echo pairs at median age 13.5 (IQR 7.7–17.9) years; 6.4% with LVEF ≤50%; 1.3% with LVEF ≤40%], 28% with leukaemia, 16% with lymphoma, 8% with neuroblastoma, 8% with sarcoma, 2% with gastrointestinal cancers, 3% with genitourinary cancers, 6% with central nervous system cancers, 11% with other/unspecified cancers, and 18% with missing/unknown cancer labels. Treatment strategies included anthracyclines (35%), bone marrow transplant (7%), and radiation (1%). The external test cohort comprised 2964 patients [55.4% male; 7054 ECG–echo pairs at median age 11.6 (IQR 6.8–15.1) years; 2.5% with LVEF ≤50%; 0.9% with LVEF ≤40%]. Similar AUROCs (0.80–0.85), sensitivities (0.75–0.82), NPVs (0.986–0.996), and percent predicted negative (51–65%) were obtained across institutions to predict LVEF ≤50%, outperforming a biomarker-based model benchmark. Patients with high AI-ECG risk scores for LVEF ≤50% had higher rates of mortality [hazard ratio 3.1 (95% CI 1.8–5.3), P < 0.001] compared to patients with low AI-ECG risk scores. Conclusion AI-ECG shows promise as a digital biomarker for cardiac surveillance in the vulnerable childhood cancer survivor population.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, CE-marked for hepatic neoplasia, offers the potential for targeted high-dose beta radiation in GBM by leveraging tumor hypervascularity. The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for recurrent GBM. MATERIAL AND METHODS FRONTIER is a prospective, single-arm, multi-center study with Investigational Device Exemption approval from the US FDA. This initial cohort included patients with recurrent GBM in non-dominant, non-eloquent regions after 1-2 lines of prior therapy. The primary endpoint was the 30-day incidence of treatment-related toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included overall treatment-related adverse events (AE), neurological function changes, technical success, and efficacy measures. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET for absorbed dose distribution, and serial neurological assessments. Changes in post-contrast T1-enhancing tissue volume (T1C-vol) were tracked longitudinally. RESULTS Twelve subjects (67% male; average age 57 years) were treated. The procedure was well-tolerated with no limiting toxicities reported or device-related AEs reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). At discharge one day after treatment, there was no decline in neurologic status per NIHSS. Technical success was 100%, with post-treatment Y90-PET showing a median absorbed dose of 41.5 Gy (range 39.2-45.4) to the treatment region (median volume 80.3 cc [40.9-118.5]). The median tumor absorbed dose was significantly higher at 124.2 Gy (range 58.5-508.5) within a median tumor volume of 5.8 cc (range 0.5-55.4), indicating preferential tumor perfusion. At 1 month, the best response was partial response in 17% (2/12), stable disease (SD) in 67% (8/12), and progressive disease in 17% (2/12). At 2 months, 73% (8/11 evaluable) had SD, and 33% (4/12) showed reduced T1C-vol within the treated area. Median progression-free survival was 3.0 (95% CI 1.1-3.7) and median overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (>124 Gy) compared to those below (13.1 vs 5.8 months, p=0.0054). CONCLUSION Results from this initial cohort of the FRONTIER trial suggest IA Y90 glass microsphere therapy is technically feasible and well-tolerated in patients with recurrent GBM. The observed dose-response relationship warrants further investigation of this modality as a potential treatment option.