Citations

The 2024 Annual Congress of the International Liver Transplantation Society (ILTS) was from May 1–4 in Houston, Texas, USA, under the theme “Liver Disease and Transplantation: Breaking Barriers and Exploring New Frontiers.” In addition to a robust scientific program, the congress also hosted a hands-on cadaveric robotic liver surgery course, a machine perfusion workshop, and a transesophageal echocardiography course. In this report, the ILTS Vanguard and Basic Sciences Committees present a summary of the congress proceedings.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis. Discovery and mechanistic understanding of the genetic and epigenetic drivers of PDAC is therefore of critical importance. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of clinical progression and demonstrate that it can have a non-canonical function as a regulator of epigenomic states of PDAC cells and associated extensive changes in gene expression. We show that SPINK1 expression, which varies in PDAC, is associated with key aggressive phenotypic cancer states and is correlated with the expression of stemness markers both in vitro and in patient samples. Mechanistically, our results strongly suggest that SPINK1 acts through a new signaling axis, by interacting with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and suggest a potential therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling.

Abstract Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Patients and Methods: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL −1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response >12 months and ongoing even after stopping treatment (5.4–69.0 months). Patients with PD-L1–positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1–negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

Abstract The TopBP1-ATR axis is critical for maintaining genomic stability during DNA replication stress, yet the precise regulation of TopBP1 in replication stress responses remains poorly understood. In this study, we identified PHD and Ring Finger Domains 1 (PHRF1) as an important ATR activator through its interaction with TopBP1. Our analysis revealed a correlation between PHRF1 and genomic stability in cancer patients. Mechanistically, PHRF1 is recruited to DNA lesions in a manner dependent on its PHD domain and histone methylation. Subsequently, PHRF1 mono-ubiquitinates TopBP1 at lysine 73, which enhances the TopBP1-ATR interaction and activates ATR. Depletion of PHRF1 disrupts ATR activation and sensitizes cells to replication stress-inducing agents. Furthermore, conditional knockout of Phrf1 in mice leads to early lethality and impaired ATR-Chk1 axis signaling. Collectively, our findings establish PHRF1 as a novel E3 ligase for TopBP1, coordinating the replication stress response by enhancing TopBP1-ATR signaling.

We describe the design and results from the BraTS 2023 Intracranial Meningioma Segmentation Challenge. The BraTS Meningioma Challenge differed from prior BraTS Glioma challenges in that it focused on meningiomas, which are typically benign extra-axial tumors with diverse radiologic and anatomical presentation and a propensity for multiplicity. Nine participating teams each developed deep-learning automated segmentation models using image data from the largest multi-institutional systematically expert annotated multilabel multi-sequence meningioma MRI dataset to date, which included 1000 training set cases, 141 validation set cases, and 283 hidden test set cases. Each case included T2, FLAIR, T1, and T1Gd brain MRI sequences with associated tumor compartment labels delineating enhancing tumor, non-enhancing tumor, and surrounding non-enhancing FLAIR hyperintensity. Participant automated segmentation models were evaluated and ranked based on a scoring system evaluating lesion-wise metrics including dice similarity coefficient (DSC) and 95% Hausdorff Distance. The top ranked team had a lesion-wise median dice similarity coefficient (DSC) of 0.976, 0.976, and 0.964 for enhancing tumor, tumor core, and whole tumor, respectively and a corresponding average DSC of 0.899, 0.904, and 0.871, respectively. These results serve as state-of-the-art benchmarks for future pre-operative meningioma automated segmentation algorithms. Additionally, we found that 1286 of 1424 cases (90.3%) had at least 1 compartment voxel abutting the edge of the skull-stripped image edge, which requires further investigation into optimal pre-processing face anonymization steps.

Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8 high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (<60 years vs ≥60 years) and disease duration (<6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (<60 years or ≥60 years) and disease duration (recent [<6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P >.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196