Citations

340 Background: TIS, an anti-programmed cell death protein 1 (PD-1) antibody, + chemo as 1L therapy demonstrated statistically significant and clinically meaningful improvement in overall survival (OS) vs PBO + chemo in patients with advanced or metastatic ESCC (hazard ratio [HR] 0.66 [95% confidence interval (CI) 0.54, 0.80]; P< 0.0001), with a manageable safety profile, at interim analysis of the phase 3, double-blind RATIONALE-306 study (NCT03783442). Here, we report data from the non-Asia subgroup (Europe, Northern America, and Oceania). Methods: Adults with advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were randomized 1:1, (stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg intravenously (IV) once every 3 weeks (Q3W) (Arm A) or PBO IV Q3W (Arm B), with platinum + fluoropyrimidine, or platinum + paclitaxel until disease progression by INV per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included: progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) by INV per RECIST v1.1; OS in the programmed death-ligand 1 score ≥10%; and safety. Results: Of 649 randomized patients, 163 (25.1%) were from the non-Asia subgroup (Arm A, n = 83; Arm B, n = 80). At data cutoff (Feb 28, 2022), the median study follow-up time in the non-Asia subgroup was 16.0 months (mo) in Arm A vs 8.4 mo in Arm B. OS (median 16.3 vs 9.0 mo; unstratified HR 0.66 [95% CI 0.45, 0.96]) and PFS (median 7.7 vs 5.5 mo; unstratified HR 0.59 [95% CI 0.41, 0.83]) were improved in Arm A vs Arm B, respectively. Arm A had higher ORR (61.4% vs 41.3%, odds ratio 2.27 [95% CI 1.21, 4.25]) and longer median DoR (7.1 mo [95% CI 5.6, 9.6] vs 5.7 mo [95% CI 3.8, 8.3]) than Arm B. More patients in Arm A vs Arm B experienced ≥1 treatment-related adverse event (TRAE; 94.0% vs 88.5%), serious TRAEs (25.3% vs 17.9%), and discontinuation due to treatment-emergent AEs (42.2% vs 35.9%, respectively). Similar proportions of patients in Arm A vs Arm B had ≥grade 3 TRAEs (56.6% vs 52.6%), and TRAEs leading to death (1.2% vs 1.3%), respectively. Conclusions: In the non-Asia subgroup, 1L TIS + chemo showed a clinically meaningful improvement in OS vs PBO + chemo in patients with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Clinical trial information: NCT03783442 .

Background: COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited. Methods: We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19. Results: We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31–462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19–2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62–2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01–2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26–2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06–2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine. Conclusions: Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

AbstractATP6AP1‐CDG is an X‐linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1‐CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N‐glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N‐glycan profiles. The aberrant N‐linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high‐mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1‐CDG patients, these results demonstrate that fractionated plasma N‐glycan profiling could be a valuable tool in diagnosis and disease monitoring.

Objective: To compare 12-month post-treatment health-related quality of life (HR-QoL) and symptom severity (SS) changes among patients with symptomatic uterine fibroids (SUF) not seeking fertility and undergo a hysterectomy, abdominal myomectomy (AM), or uterine artery embolization (UAE). Materials and Methods: The Comparing Options for Management: Patient-Centered Results for Uterine Fibroids (COMPARE-UF) Registry is a multi-institutional prospective observational cohort study of patients treated for SUF. A subset of 1465 women 31–45 years of age, who underwent either hysterectomy ( n = 741), AM ( n = 446), or UAE ( n = 155) were included in this analysis. Demographics, fibroid history, and symptoms were obtained by baseline questionnaires and at 1 year post-treatment. Results were stratified by all treatments and propensity score weighting to adjust for differences in baseline characteristics. Results: Women undergoing UAE reported the lowest baseline HR-QoL and highest SS scores (mean = 40.6 [standard deviation (SD) = 23.8]; 62.3 [SD = 24.2]) followed by hysterectomy (44.3 [24.3]; 59.8 [SD = 24.1]). At 12 months, women who underwent a hysterectomy experienced the largest change in both HR-QoL (48.7 [26.2]) and SS (51.9 [25.6]) followed by other uterine-sparing treatments. Propensity score weighting revealed all treatments produced substantial improvement, with hysterectomy patients reporting the highest HR-QoL score (92.0 [17.8]) compared with myomectomy (86.7 [17.2]) and UAE (82.6 [21.5]) ( p < 0.0001). Similarly, hysterectomy patients reported the lowest SS scores (8.2 [15.1]) compared with myomectomy (16.5 [15.1]) and UAE (19.6 [17.5]) ( p < 0.0001). Conclusion: All procedures showed improvement in HR-QoL and reduction in SS score at 12 months, hysterectomy showing maximum improvement. Of importance, at 12 months, patients who underwent either a myomectomy or UAE reported comparable symptom relief and HR-QoL. Clinicaltrials.Gov Identifier: NCT02260752.

Abstract Introduction: Mammographic breast density is among the strongest risk factors for breast cancer. However, breast density is typically assessed subjectively by the radiologist according to the Breast Imaging Reporting and Data System (BI-RADS) based on 2 dimensional (2D) digital mammography (DM) images. Digital breast tomosynthesis (DBT) is quickly replacing DM and allows more detailed volumetric imaging of the breast. Advances in radiomics, the high-throughput extraction of radiologic features, has enabled characterization of breast parenchymal complexity beyond breast density alone. The purpose of this study was to compare the performance of volumetric parenchymal pattern analysis from DBT and DM with conventional breast density measurement with respect to breast cancer risk estimation. Methods: We performed a case control study among women with concurrent DM and DBT screening (Selenia Dimensions, Hologic Inc.) at our institution between 3/2011-12/2014. Cases were diagnosed with breast cancer within 1 year of screening; controls were confirmed negative or benign at 1 year follow-up, matched on race (Black, White, other/unknown) and age (5-year bins). After exclusions for imaging artifacts, craniocaudal (CC) and mediolateral oblique (MLO) views for 187 cases and 737 controls, in six image formats were assessed: 1) raw (“FOR PROCESSING”) DM; 2) processed (“FOR PRESENTATION”) DM; 3) raw DBT central projection; 4) processed DBT central projection; 5) DBT central reconstructed slice; and 6) DBT reconstructed stack. For cases, we analyzed the breast contralateral to cancer diagnosis; for controls the same breast as the matched case. We extracted radiomic features using a lattice-based approach with the publicly available CaPTk software, averaging features for each breast over CC and MLO views. We examined 3 lattice window sizes (6.4, 12.8, and 25.6 mm) and 23 resolutions for image resampling (0.075 - 2mm). We performed PCA on the resulting 487 features for each combination of window size and resolution and built conditional logistic regression models to assess the association of the first 7 principal components with breast cancer, with models including age, BMI, and BI-RADS density. For each image type we calculated the model C-statistic at all window sizes and resolutions, for a total of 2304 experimental conditions. Results: Features from reconstructed DBT scans had on average higher C-statistics across all experimental conditions. A model using only age, BMI, and BI-RADS density had a C-statistic of 0.61. Models using radiomic features plus age, BMI, and BI-RADS density had mean C-statistic of 0.68 (IQR 0.68, 0.69) for reconstructed DBT scans; for all other image types, the mean C-statistic ranged from 0.64 to 0.66. Conclusions: Incorporating volumetric breast parenchymal patterns from DBT improves breast cancer risk estimation beyond markers derived from DM and beyond conventional BI-RADS density. Citation Format: Eric A. Cohen, Omid Haji Maghsoudi, Raymond Acciavatti, Lauren Pantalone, Walter Mankowski, Alex A Nguyen, Christopher G. Scott, Stacey Winham, Andrew D. Maidment, Anne Marie McCarthy, Celine M Vachon, Emily F Conant, Despina Kontos. Volumetric parenchymal pattern analysis for breast cancer risk estimation. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P070.

Abstract In susceptible mouse strains, the wild-type Daniel’s (wt-DA) strain of Theiler’s murine encephalomyelitis virus induces a persistent central nervous system (CNS) infection with chronic demyelination. The virus is cleared from resistant mice with no resulting demyelination. We characterized the role of the DA L* protein in late demyelination and persistent infection. The DA genome has two alternative reading frames, encoding the virus polyprotein and L*, respectively. The mutant virus DAL*-1 fails to synthesize L* and does not persist in the CNS of wt-DA-susceptible SJL/J or B10.S mice. Since class I-restricted cytotoxicity has been shown to determine resistance to virus persistence and demyelination in this model, virus-specific cytotoxicity in the CNS of DA-resistant (B6 or B10) and -susceptible (SJL/J and B10.S) mice during the acute stage of DA and DAL*-1 infection was characterized. Following intracerebral inoculation with DAL*-1, virus-specific Db- and Kb-restricted CTLs were demonstrated in the CNS of resistant B10 mice, whereas only Db-restricted CTL were found in wt-DA-inoculated mice. CTLs specific to wt-DA or DAL*-1 recognized class I-presented peptides from either of the viruses. Of particular interest, Ks-restricted virus-specific cytotoxicity-restricted CTLs were identified in the CNS of susceptible SJL/J (H-2s) and B10.S (H-2s) mice inoculated with DAL*-1. In contrast, no virus-specific CTLs were identified in the CNS of SJL/J and B10.S mice inoculated with wt-DA. We propose that L* inhibits the generation of H-2K-restricted virus-specific cytotoxicity in the CNS, permitting a persistent infection in susceptible strains, with subsequent inflammatory demyelination in the CNS similar to that in human multiple sclerosis.

Abstract The role of IL-1 in augmenting the Ag receptor-initiated activation program was evaluated in IL-4-producing (Th2) CD4+ murine T lymphocytes. Northern blot and 125I-labeled IL-1 alpha cross-linking analyses demonstrated that Th2 lymphocytes express both type I and type II IL-1R. The expression of both IL-1R isoforms on the surface of the Th2 cells is coordinately up-regulated in response to anti-CD3 cross-linking in the absence of detectable accessory cells. Analyses of the kinetics of IL-1R acquisition demonstrated that the peak level of type I and type II IL-1R mRNA expression occurs after the peak expression of mRNA encoding IL-2R alpha and IL-4, which are two IL-1-responsive events in the Th2 activation program. Type I IL-1R ligand-binding antagonists, IL-1R antagonist and anti-type I mAb, were used to evaluate the functional significance of Th2 cell expression of two IL-1R isoforms. The addition of either IL-1R antagonist or anti-type I mAb completely inhibited the IL-1 alpha-augmented component of the proliferative response stimulated by anti-CD3 plus exogenous IL-1 alpha. Together, these studies indicate that, although Th2 clones express inducible levels of both type I and type II IL-1R isoforms, the IL-1-induced intracellular signals involved in augmenting an anti-CD3-stimulated proliferative response are mediated solely through the type I IL-1R.

Abstract Aim There are limited data on the impact of 2 vs 3 doses of COVID-19 vaccine in patients with inflammatory bowel disease (IBD). The primary aim of the study was to assess the efficacy of COVID-19 vaccine based on number of administered doses in patients with IBD. Methods We conducted a retrospective cohort study using TriNetX, a multi-institutional database to compare patients with IBD who received 1, 2, or 3 doses of BNT162b2 or mRNA-1273 to unvaccinated IBD patients (1.1.2020-7.26.2022) to assess the risk of COVID-19 after 1:1 propensity score matching. We also evaluated the impact of vaccine on a composite of severe COVID-19 outcomes including hospitalization, intubation, intensive care unit care, acute kidney injury, or mortality. Results After propensity score matching, vaccinated patients with 2 (adjusted OR [aOR], 0.8; 95% confidence interval [CI], 0.6-0.9) and 3 doses (aOR, 0.7; 95% CI, 0.5-0.9) were found to have a lower risk of COVID-19 compared with unvaccinated patients. Vaccinated patients with IBD had a lower risk of severe COVID-19 outcomes (aOR, 0.7; 95% CI, 0.6-0.9) compared with unvaccinated patients. There was no difference in the risk of COVID-19 in IBD patients with 2 compared with 3 doses (aOR, 0.97; 95% CI, 0.7-1.3). However, IBD patients with 2 doses were at an increased risk for hospitalization due to COVID-19 (aOR, 1.78; 95% CI, 1.02-3.11) compared with those that received 3 doses. Conclusion Vaccinated patients with IBD had a lower risk of severe COVID-19 outcomes compared with unvaccinated patients. A third dose of COVID-19 vaccine compared with 2 doses decreases the risk of hospitalization but not breakthrough infection in patients with IBD.

Objective To present the design and methodology for an actively enrolling comparative effectiveness study of revision palatoplasty versus pharyngoplasty for the treatment of velopharyngeal insufficiency (VPI) Design Prospective observational multicenter study Setting Twelve hospitals across the United States and Canada Participants Individuals who are 3–23 years of age with a history of repaired cleft palate and a diagnosis of VPI, with a total enrollment target of 528 participants Interventions Revision palatoplasty and pharyngoplasty (either pharyngeal flap or sphincter pharyngoplasty), as selected for each participant by their treatment team Main Outcome Measure(s) The primary outcome is resolution of hypernasality, defined as the absence of consistent hypernasality as determined by blinded perceptual assessment of a standard speech sample recorded twelve months after surgery. The secondary outcome is incidence of new onset obstructive sleep apnea. Statistical analyses will use propensity score matching to control for demographics, medical history, preoperative severity of hypernasality, and preoperative imaging findings. Results Study recruitment began February 2021. As of September 2022, 148 participants are enrolled, and 78 have undergone VPI surgery. Enrollment is projected to continue into 2025. Collection of postoperative evaluations should be completed by the end of 2026, with dissemination of results soon thereafter. Conclusions Patients with VPI following cleft palate repair are being actively enrolled at sites across the US and Canada into a prospective observational study evaluating surgical outcomes. This study will be the largest and most comprehensive study of VPI surgery outcomes to date.