Global Cohort Research Articles

Regorafenib in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in real-world practice in the United States (US): Final analysis of the prospective, observational REFINE study.

e16114 Background: In the observational REFINE study of regorafenib (NCT03289273) in pts with uHCC, treatment-emergent adverse events (TEAEs) were consistent with those reported in the global, phase 3 RESORCE trial (YJ Kim, ILCA 2022). Median overall survival (OS) in the overall global cohort of REFINE was 13.2 months; here, we present the final analysis of the US pt cohort. Methods: REFINE was an international, prospective, multicenter study that enrolled pts with uHCC for whom a decision to treat with regorafenib was made by the treating physician prior to enrollment, according to the local health authority approved label. The primary objectives were safety, including incidence of TEAEs (MedDRA v25) and dose modifications due to TEAEs. Secondary endpoints included OS, progression-free survival (PFS), and duration of treatment (DoT). Results: Of the 1005 evaluable pts from the global cohort, 65 pts (6%) were from the USA. In the US cohort, 78% were male, 69% had ECOG PS 0/1, and the population was younger than the global cohort (54% were aged <65 years vs 45% in the global cohort). The most common HCC etiology was hepatitis C in the US cohort (52% vs 24% in the global cohort) and the second most common was alcohol use (34% vs 25% in the global cohort). A lower proportion of US pts had extrahepatic spread compared with the global cohort (48% vs 59%), while a similar proportion had vascular invasion (both 34%). Use of prior immune checkpoint inhibitors was more frequent in US pts than in the overall global cohort (25% vs 10%). Most US pts (88%) had received prior sorafenib, consistent with the global cohort (96%). However, a relatively lower proportion of pts received regorafenib as a second-line therapy (71% vs 84% in the global cohort). Transarterial chemoembolization was the most common prior non-systemic treatment (42%). Median DoT was 3.1 months (range <0.1–24.6 months) in US pts vs 3.7 months (range <0.1–38.9 months) in the global cohort. TEAEs were reported in 91% of US pts and apart from a lower incidence of diarrhea and hand–foot skin reaction (HFSR) in US pts, incidences of TEAEs were comparable to the global cohort. In addition, TEAEs resulting in dose modification were relatively lower in US pts (38% vs 45% in the global cohort). Median OS in US pts was 11.4 months (95% CI 8.4, 18.0), similar to that reported for the global cohort (median OS 13.2 months [95% CI 11.6, 14.8]). Conclusions: The REFINE real-world study confirmed the safety and effectiveness of regorafenib in a broader population of pts than in the RESORCE trial. The findings remained consistent in US pts with uHCC. Clinical trial information: NCT03289273 . [Table: see text]

Tebentafusp (tebe) in a real-world cohort of 72 French metastatic uveal melanoma (UM) patients (pts).

e21583 Background: Up to 50% of UM pts will develop metastases with poor overall survival (OS) and limited treatment options. Tebe, a bispecific T-cell engager binding CD3 and the gp100 protein presented by the HLA A*02-01, recently showed a benefit in overall response rate (ORR), progression-free survival (PFS) and OS in HLA A*02-01pos metastatic UM (mUM) pts in the IMCgp100-202 phase III trial. Prior to the EMA approval, French Health Authorities allowed an early access to tebe in May 2021 to UM metastatic pts. We here report our real-world experience with tebe in metastatic UM pts. Methods: Ongoing ambispective cohort of mUM pts treated with tebe in France. Metastases are evaluated according to RECIST 1.1 with assessments every 12 weeks (liver MRI +/- CT-scan). ORR, PFS, OS and toxicities are retrieved. Results: 72 pts started tebe between May 26th 2021 and December 12th 2022 (29 men and 43 women). Median age was 61 yo (32-78). Thirty, 34 and 7 patients underwent enucleation proton beam therapy or brachytherapy, respectively (one pt did not receive local treatment). The median time to first metastasis was 24 months (0-276). Tebe was prescribed in first-line in 46 patients, in second-line or more in 26 patients. Metastatic sites at tebe initiation were liver, lung, skin, bone and muscle in 71, 4, 2, 3 and 2 patients, respectively. Liver was the sole metastatic site in 63/72 patients (87.5%). With a median follow-up of 44 weeks, patients received a median of 36 weeks of tebe. Thirty patients discontinued tebe because of disease progression, two because of poor health status and none for toxicity. Of 60 assessable pts, 33 (55%) pts showed stable disease and 5 (8%) showed partial response as best response according to RECIST 1.1. Median PFS was 28 weeks (confidence interval 95% [CI95%]: 8-56) in the global cohort. OS at 12 months was 74% ([CI95%] = 0.62-0.89) in the global cohort, 73% ([CI95%] = 0.55-0.99) and 74% ([CI95%] = 0.57-0.97) in 1st and 2nd line and more, respectively. To date, 13 pts died. Circulating tumor DNA analyses and monitoring of peripheral blood leukocytes are ongoing and will be available by June 2023. Conclusions: In this ongoing, real-world, cohort of metastatic UM pts, tebe is associated with similar clinical outcomes as in the IMCgp100-202, phase III trial. Translational studies on blood and tumor samples are ongoing to identify predictive biomarkers of clinical benefit to this drug.

A multicenter study on adjuvant chemotherapy of S-1 versus observation for resected perihilar cholangiocarcinoma.

e16201 Background: The prognosis of perihilar cholangiocarcinoma (PHC) is poor even after curative resection. The efficacy of adjuvant S-1 chemotherapy for resected PHC is unclear. This study aimed to assess the efficacy of adjuvant S-1 chemotherapy after major hepatectomy for PHC. Methods: Consecutive patients with PHC who underwent major hepatectomy (hemihepatectomy or trisectionectomy extending to segment 1 with extrahepatic bile duct resection) at three high-volume centers in Japan from 2007 to 2020 were retrospectively evaluated. Patients with Clavien-Dindo grade V complications, pStage I or IVB disease, and those who underwent adjuvant radiation therapy were excluded from analysis. Propensity score matching analysis was performed to compare the disease-specific survival (DSS) of patients who underwent adjuvant S-1 chemotherapy with those who underwent observation. Results: Of 480 patients, 373 were eligible for the study, 81 of whom underwent adjuvant S-1 chemotherapy, and 146 underwent observation. In the global cohort, DSS in the S-1 and observation groups were similar ( P = 0.18). In the matched cohort as well (S-1: n=44, Observation: n=44), DSS was similar between the S-1 and observation groups ( P = 0.09). On multivariate analysis, performance of percutaneous biliary drainage, CA19-9 levels at operation ≥ 300 U/ml, and lymph node (LN) metastasis were independent predictors of poor survival following major hepatectomy for PHC. In subgroup analysis of patients with LN metastasis, DSS in the S-1 group was better than in the observation group ( P = 0.001). Conclusions: Adjuvant S-1 chemotherapy after major hepatectomy might be effective in PHC patients with LN metastasis.

Genomic biomarker testing and treatment in advanced NSCLC: Practice patterns and barriers in a global survey of oncology point-of-care mobile app users.

e21004 Background: Appropriate molecular testing and oncogene-directed treatment planning are essential best practices for managing patients with advanced non-small cell lung cancer (aNSCLC) who are potential candidates for targeted therapy. Understanding real-world practices and challenges among oncology health care professionals (HCPs) is necessary to inform the development of digital tools and other initiatives that support optimal care. Methods: From 12/2022 to 01/2023, 142 HCPs who treat aNSCLC completed an online survey related to NSCLC genomic biomarker testing and treatment planning. Participants were recruited from a global cohort of HCPs who are active users of an oncology point-of-care mobile app following the launch of an NSCLC decision-support tool and educational intervention. Results: Participants included medical oncologists (87%), surgical oncologists (3%), pulmonologists (2%), and nurses (4%) from 62 countries. Most (72%) reported providing care for ≥5 pts/month with aNSCLC; 27.5% provide care for ≥20 pts/month. HCPs reported testing the following genomic biomarkers in 100%, 50-99%, 1-49%, and 0% of patients with aNSCLC, respectively: EGFR (44%, 23%, 27%, 4%), ALK (41%, 20%, 29%, 8%), ROS1 (32%, 19%, 23%, 22%), BRAF (23%, 20%, 23%, 31%), NTRK (12%, 14%, 22%, 47%), HER2 (11%, 17%, 27%, 42%), KRAS (23%, 15%, 25%, 33%), RET (13%, 13%, 25%, 44%), MET exon 14 (15%, 12%, 27%, 42%). Reported barriers varied in frequency (Table 1), with the most common involving biomarker test turnaround time. The majority of HCPs reported often or sometimes feeling that “results take too long,” and they (80%) and/or their patients (81%) are eager to start treatment. HCPs also commonly reported often or sometimes not being sure about which tests to order (45%), when to test (43%), which 1st-line therapy to select (45%), which 2nd- or later-line therapy to select (57%), and how to manage adverse events of oncogene-targeted therapy (50%). Conclusions: In current real-world practice, the majority of HCPs report suboptimal testing for targetable genomic alterations ( EGFR, ALK, ROS1, BRAF, NTRK, HER2, KRAS, RET, and MET exon 14) in patients with aNSCLC. Identified common barriers represent opportunities for future interventions to improve biomarker-directed NSCLC care. [Table: see text]

Variation of body composition and its impact on survival in a global population of patients receiving multimodal treatment for esophageal cancer.

e16093 Background: Growing evidence has supported a role for body composition in predicting survival in patients undergoing esophagectomy. This study seeks to define baseline variation and clinical correlates of body composition in an international cohort of patients undergoing esophagectomy for cancer. Methods: Patients who underwent esophagectomy in fourteen high-volume centers between January 2007 to December 2019 were eligible for inclusion. Skeletal muscle, visceral and subcutaneous adipose tissues within CT images, acquired at the time of diagnosis, were analyzed by a single trained assessor in accordance with a standardized protocol. Survival status was censored June 2022. Results: In total 1716 patients were recruited to this study from three global regions: North America (n = 386; 22.5%), Europe (n = 940; 54.8%) and Asia (n = 390; 22.7%). Patients were predominantly male (79.5%) and adenocarcinoma was the most common histological subtype (66.6%). Wide variation in skeletal muscle (17.1 to 83.5cm2), visceral (0.2 to 170.1cm2) and subcutaneous adipose tissue (0.2 to 216.8cm2) was observed. Characteristics that were significantly associated with levels of muscle and adiposity were global region, sex, age and histological subtype. Compared to adenocarcinoma, SCC was associated with significantly (p < .0001) lower levels of muscle and adiposity, a finding that was independent of global region, sex, and age using a multivariable linear regression model (p < .0001). Reduced skeletal muscle and an excess of total adiposity at the time of diagnosis was associated with 90-day mortality and worse long-term survival. A nomogram including skeletal muscle, total adiposity at diagnosis and other tumor and patient specific variables was constructed to allow convenient survival prediction. Conclusions: This is the first study to assess parameters of body composition in a global cohort of patients receiving multimodal therapy for esophageal cancer. Findings highlight important regional and disease specific variation in body composition parameters and demonstrate the clinical utility of these measurements in predicting both early and late survival after esophagectomy. Results are intended to inform future guidelines for the use of body composition assessment in routine clinical practice.

OS-065-YI - Predictors of severe flares after nucleos (t)ide analogue cessation-results of a global cohort study (RETRACT-B study)

OS-065-YI - Predictors of severe flares after nucleos (t)ide analogue cessation-results of a global cohort study (RETRACT-B study)

Global disparities in the treatment of idiopathic inflammatory myopathies: results from an international online survey study.

We aimed to explore current practice and interregional differences in the treatment of idiopathic inflammatory myopathies (IIMs). We triangulated these observations considering countries' gross national income (GNI), disease subtypes, and symptoms using patient-reported information. A cross-sectional ancillary analysis of the 'COVID-19 vaccination in auto-immune disease' (COVAD) e-survey containing demographic characteristics, IIM subtypes (DM, PM, IBM, anti-synthetase syndrome [ASSD], immune-mediated necrotizing myopathy [IMNM], overlap myopathies [OM]), current symptoms (surrogate for organ involvement) and treatments (corticosteroids [CS], immunomodulators [IM], i.e. antimalarials, immunosuppressants [IS], IVIG, biologic treatments and targeted-synthetic small molecules). Treatments were presented descriptively according to continents, GNI, IIM and organ involvement, and associated factors were analysed using multivariable binary logistic regressions. Of 18 851 respondents from 94 countries, 1418 with IIM were analysed (age 61 years, 62.5% females). DM (32.4%), IBM (24.5%) and OM (15.8%) were the most common subtypes. Treatment categories included IS (49.4%), CS (38.5%), IM (13.8%) and IVIG (9.4%). Notably, treatments varied across regions, GNI categories (IS mostly used in higher-middle income, IM in lower-middle income, IVIG and biologics largely limited to high-income countries), IIM subtypes (IS and CS associated with ASSD, IM with OM and DM, IVIG with IMNM, and biologic treatments with OM and ASSD) and disease manifestations (IS and CS with dyspnoea). Most inter-regional treatment disparities persisted after multivariable analysis. We identified marked regional treatment disparities in a global cohort of IIM. These observations highlight the need for international consensus-driven management guidelines considering patient-centred care and available resources.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Comparative Genomic Landscape of Urothelial Carcinoma of the Bladder Among Patients of East and South Asian Genomic Ancestry.

Despite the low rate of urothelial carcinoma of the bladder (UCB) in patients of South Asian (SAS) and East Asian (EAS) descent, they make up a significant portion of the cases worldwide. Nevertheless, these patients are largely under-represented in clinical trials. We queried whether UCB arising in patients with SAS and EAS ancestry would have unique genomic features compared to the global cohort. Formalin-fixed, paraffin-embedded tissue was obtained for 8728 patients with advanced UCB. DNA was extracted and comprehensive genomic profiling was performed. Ancestry was classified using a proprietary calculation algorithm. Genomic alterations (GAs) were determined using a 324-gene hybrid-capture-based method which also calculates tumor mutational burden (TMB) and determines microsatellite status (MSI). Of the cohort, 7447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. When compared with EUR, TERT GAs were less frequent in SAS (58.1% vs. 73.6%; P = .06). When compared with non-SAS, SAS had less frequent GAs in FGFR3 (9.5% vs. 18.5%, P = .25). TERT promoter mutations were significantly less frequent in EAS compared to non-EAS (54.1% vs. 72.9%; P < .001). When compared with the non-EAS, PIK3CA alterations were significantly less common in EAS (12.7% vs. 22.1%, P = .005). The mean TMB was significantly lower in EAS vs. non-EAS (8.53 vs. 10.02; P = .05). The results from this comprehensive genomic analysis of UCB provide important insight into the possible differences in the genomic landscape in a population level. These hypothesis-generating findings require external validation and should support the inclusion of more diverse patient populations in clinical trials.

Abstract 720: Integration Of Population Genetic And Human Knockout Studies With Smooth Muscle Cell Lineage Tracing In Mouse Models Identifies Novel Targets For Atherosclerosis And Cardiovascular Risk.

Despite lipid-lowering therapies, residual cardiovascular disease risk remains a major unmet clinical need. Large-scale genetic analyses have identified &gt;250 loci for coronary artery disease (CAD) risk. Genes that function in vascular smooth muscle cells (SMC) are causal at several loci, yet the causal genes at most loci remain unknown. Using single cell profiling and SMC lineage tracing in mouse models, we and others have shown that SMC transition through an intermediate state to SMC-derived cells (SDC) with protective or harmful phenotypes for plaque stability. In this study, we integrated SMC lineage tracing in mouse models with ongoing analyses in &gt; 1 million human participants with whole-genome (WGS) and whole-exome sequencing (WES) data, as well as rare variant analysis of human “knockouts” (homozygous for predicted loss-of-function variants) for a novel gene discovery pipeline (Figure 1). Through WES in 76,000 highly consanguineous participants in the Pakistan Genomic Resource (PGR), we assembled the largest global cohort of human KOs. At non-lipid CAD loci from a recent large multi-ethnic meta-analysis (~1.1 million participants), we prioritized genes as potentially causal in SMC/SDC as those that are expressed and regulated in human or mouse arteries and SMC in atherosclerosis progression. Through gene burden testing and analyses of rare predicted loss-of-function (pLoF) and damaging (pDMs) variants in the largest CAD WES/WGS meta-analyses we enriched for causal genes. We restricted to genes with at least 5 pLoF carriers in PGR to facilitate recall studies in Pakistan. Final prioritization incorporated state-of-the-art fine mapping and co-localization analyses as well as biological plausibility. From an initial pool of 1696 genes, our gene discovery pipeline prioritized 15 SMC/SDC genes, and initial recall in PGR identified multiple large pedigrees for mutations in candidate causal genes PDE3A, SERPINH1, HHIPL1, and ZEB2.

CT Perfusion in Lacunar Stroke: A Systematic Review.

The main theory underlying the use of perfusion imaging in acute ischemic stroke is the presence of a hypoperfused volume of the brain downstream of an occluded artery. Indeed, the main purpose of perfusion imaging is to select patients for endovascular treatment. Computed Tomography Perfusion (CTP) is the more used technique because of its wide availability but lacunar infarcts are theoretically outside the purpose of CTP, and limited data are available about CTP performance in acute stroke patients with lacunar stroke. We performed a systematic review searching in PubMed and EMBASE for CTP and lacunar stroke with a final selection of 14 papers, which were examined for data extraction and, in particular, CTP technical issues and sensitivity, specificity, PPV, and NPV values. A global cohort of 583 patients with lacunar stroke was identified, with a mean age ranging from 59.8 to 72 years and a female percentage ranging from 32 to 53.1%.CTP was performed with different technologies (16 to 320 rows), different post-processing software, and different maps. Sensitivity ranges from 0 to 62.5%, and specificity from 20 to 100%. CTP does not allow to reasonable exclude lacunar infarct if no perfusion deficit is found, but the pathophysiology of lacunar infarct is more complex than previously thought.

Siponimod Stabilizes Physical Disability Scores in People Living With Secondary Progressive Multiple Sclerosis After 2 Years of Treatment: Analysis From the Novartis Global Managed Access Program (P8-3.010)

<h3>Objective:</h3> To describe demographic and clinical characteristics and characterize change in Expanded Disability Status Scale (EDSS) score in people living with secondary progressive multiple sclerosis (plwSPMS) receiving siponimod under the managed access program (MAP; Global Siponimod MAP cohort [BAF2001M cohort]). <h3>Background:</h3> Siponimod significantly reduced the risk of confirmed disability progression and worsening of cognitive processing speed vs placebo in the phase 3 EXPAND trial (NCT01665144). However, real-world effectiveness data for siponimod remain scarce. <h3>Design/Methods:</h3> The BAF2001M cohort is an umbrella program to facilitate access to siponimod when marketing authorization is pending (under physician request) in the absence of acceptable alternative treatments. The program started in March 2019 and is ongoing. The target population included adult patients with SPMS and an EDSS score &lt;7 from March 2019 to January 2021. After January 2021, access to the MAP required SPMS with active disease. Treatment selection and patient monitoring were based on physician assessment. Baseline characteristics included country, age, sex, relapse, MRI activity in the last 2 years, EDSS, and cognition evaluation. <h3>Results:</h3> A total of 632 cases were analyzed (153 excluded from analysis due to local country restrictions). Mean (SD) age was 52.3 (8.7) years, 60% of patients were female, and median (IQR) EDSS was 5.5 (4.5–6.5). Prior to siponimod start, ~51% experienced a relapse in the last 2 years, 54% had previous cognitive evaluation, and 52% had an MRI scan in the last 2 years (48% showed activity). Mean change in EDSS from baseline was approximately −0.02/−0.03 at Months 6, 12, 18, and 24 (not significantly different vs baseline). Approximately 94% (140/149) of patients improved or were stable at Month 24. <h3>Conclusions:</h3> Most plwSPMS demonstrated improved or stabilized EDSS scores over 2 years. This population was older than the EXPAND study population and around half demonstrated relapse/MRI activity. Results support the effectiveness of siponimod in SPMS. <b>Disclosure:</b> Dr. Mavrikis Cox has received personal compensation for serving as an employee of Novartis Pharmaceuticals. Dr. Mavrikis Cox has stock in Novartis Pharmaceuticals. Virginia DeLasHeras has nothing to disclose. Dr. Ryan has received personal compensation for serving as an employee of Novartis. Mrs. Istrate has nothing to disclose. Soudeh Ansari has received personal compensation for serving as an employee of Novartis. Sophie Arnould has nothing to disclose. Dr. Piani Meier has received personal compensation for serving as an employee of Novartis. Dr. Piani Meier has received personal compensation for serving as an employee of Merck Group.

Abstract CT266: Chinese race and origin have no clinically meaningful effect on tiragolumab and atezolizumab pharmacokinetics and safety in patients with advanced solid tumors

Abstract Background: Tiragolumab is a fully human IgG1 monoclonal antibody targeting the immune checkpoint TIGIT and is under evaluation in combination with anti-PD-L1 (atezolizumab) therapy. Here we report PK, safety, and preliminary anti-tumor activity from a Phase I open-label study (YP42514, CTR20210219) evaluating tiragolumab + atezolizumab in Chinese patients (pts) with advanced or metastatic solid tumors. Methods: Pts ≥18 years of age with an ECOG performance status of 0 or 1, a life expectancy of ≥12 weeks, adequate hematologic and end organ function who were residents in mainland China were eligible. Pts received tiragolumab 600 mg + atezolizumab 1200 mg IV every 3 weeks. Serial PK sampling was obtained in the first dosing Cycle on Days 1, 2, 8, 15, and 21, followed by sparse peak and trough collection. PK parameters were assessed by noncompartmental analysis and summarized using descriptive statistics. The severity of adverse events (AEs) was assessed using NCI CTCAE v5. Confirmed overall response rate and duration of response (DOR) were determined by investigator. Data cutoff: Feb 10, 2022. To support the dosing approach, findings in the current study were compared with results of a global Phase I study GO30103 (NCT02794571) [Bendell JC, et al. Cancer Res 2020;80:(suppl 16; Abst CT302)] in pts from France, Korea, Spain, the United States, Canada, and Australia receiving the same combination and dosing regimen. Results: Twenty Chinese pts were enrolled and received a median of 5 doses of tiragolumab + atezolizumab. Pts had a median age of 57.5 (range 44-73) years, were mostly male (85%), had a median of ≥2 prior lines of therapy and 30% of pts received prior immunotherapy. Non-small cell lung cancer was the most common tumor type (55%). Exposures in Chinese pts were comparable to the global population, with a geometric mean ratio (GMR) of 1.07 for Cycle 1 tiragolumab area under the concentration-time curve from 0 to 21 days, and a GMR of 0.92 and 0.93 for Cycle 1 peak and trough atezolizumab exposure, respectively. The frequency of treatment-related AEs, all-cause grade 3/4 AEs, grade 3/4 AEs of special interest, and AEs leading to withdrawal from study treatment were generally similar for pts in China (85.0%, 40%, 10%, and 5.0%) and those in the global GO30103 study (71.3%, 41.7%, 5.3%, and 5.6%). Treatment exposure was similar in the YP42514 study vs the respective global GO30103 cohort. Two Chinese pts (10%) had a partial response, their DORs were 3 and 6 months (censored), and seven pts (35%) had stable disease. Conclusions: Tiragolumab + atezolizumab was tolerable with preliminary anti-tumor activity. No meaningful differences in the PK or safety profile of tiragolumab + atezolizumab were seen between Chinese and global populations. Citation Format: Colby Shemesh, Yongsheng Wang, Andrew An, Hao Ding, Phyllis Chan, Qi Liu, Yih-Wen Chen, Benjamin Wu, Qiong Wu, Xian Wang. Chinese race and origin have no clinically meaningful effect on tiragolumab and atezolizumab pharmacokinetics and safety in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT266.

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. Acellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

MELD 3.0 adequately predicts mortality and renal replacement therapy requirements in patients with alcohol-associated hepatitis

Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20-33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732-0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713-0.775; p= 0.042) and Maddrey's discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691-0.757; p= 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723-0.783; p= 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727-0.788; p= 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724-0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708-0.770; p= 0.028) and mDF (AUC:0.717, 95% CI: 0.687-0.748; p= 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805-0.883). MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.

Effect of host factors and COVID-19 infection on the humoral immune repertoire in treated HIV.

People with HIV (PWH) appear to be at higher risk for suboptimal pathogen responses and for worse COVID-19 outcomes, but the effects of host factors and COVID-19 on the humoral repertoire remain unclear. We assessed the antibody isotype/subclass and Fc-receptor binding Luminex arrays of non-SARS-CoV-2 and SARS-CoV-2 humoral responses among antiretroviral therapy-treated (ART-treated) PWH. Among the entire cohort, COVID-19 infection was associated with higher cytomegalovirus (CMV) responses (vs. the COVID- cohort ), potentially signifying increased susceptibility or a consequence of persistent inflammation. Among the COVID+ participants, (a) higher BMI was associated with a striking amplification of SARS-CoV-2 responses, suggesting exaggerated inflammatory responses, and (b) lower nadir CD4 was associated with higher SARS-CoV-2 IgM and FcγRIIB binding capacity, indicating poorly functioning extrafollicular and inhibitory responses. Among the COVID-19- participants, female sex, older age, and lower nadir CD4 were associated with unique repertoire shifts. In this first comprehensive assessment of the humoral repertoire in a global cohort of PWH, we identify distinct SARS-CoV-2-specific humoral immune profiles among PWH with obesity or lower nadir CD4+ T cell count, underlining plausible mechanisms associated with worse COVID-19-related outcomes in this setting. Host factors associated with the humoral repertoire in the COVID-19- cohort enhance our understanding of these important shifts among PWH.

Nadir Prostate-specific Antigen as an Independent Predictor of Survival Outcomes: A Post Hoc Analysis of the PROSPER Randomized Clinical Trial.

This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.

EARLIER GAINS IN ACTIVE RANGE OF MOTION FOLLOWING ROBOTIC-ASSISTED TOTAL KNEE ARTHROPLASTY COMPARED WITH CONVENTIONAL INSTRUMENTATION

We sought to evaluate the early post-operative active range-of-motion (AROM) between robotic-assisted total knee arthroplasty (raTKA) and conventional TKA (cTKA). A secondary data analysis on a global prospective cohort study was performed. A propensity score method was used to select a matched control of cTKA from the same database using 1:1 ratio, based on age, sex, BMI, and comorbidity index. This resulted in 216 raTKA and cTKA matched cases. Multivariable longitudinal regression was used to evaluate difference in ROM over time and values are reported as least squares means (95% confidence interval). The longitudinal model tested the treatment effect (raTKA vs cTKA), time effect, and their interaction with control on covariance of patients ‘s age, sex, BMI, comorbidity and pre-operative flexion. Logistic regression was used to analyze the active flexion level at one month (cut by 90°) and three months (cut by 110°).At one-month postoperative the raTKA cases had more AROM for flexion by an average of 5.54 degrees (p&lt;0.001). There was no difference at three months (p=0.228). The raTKA group had a greater improvement from pre-operative values at both one-month, with an average 7.07° (3.6°, 10.5°, p&lt;0.001) more improvement, and at three-months with an average improvement of 4° more (1.61°, 7.24°, p=0.0115). AROM for extension was lower overall in the raTKA group by an average of 0.44° (p=0.029). The raTKA patients had higher odds of achieving ≥90° of flexion at one-month (OR 2.15, 95% CI 1.16, 3.99).raTKA resulted in greater AROM flexion gains in the early postoperative period than cTKA. Additional research is needed to understand if these earlier gains in AROM are associated with improved patient satisfaction and continued improvements with time.

A Single-lead ECG algorithm to differentiate right from left manifest accessory pathways: A reappraisal of the P-Delta interval.

Despite numerous ECG algorithms being developed to localize the site of manifest accessory pathways (AP), they often require stepwise multiple-lead analysis with variable accuracy, limitations, and reproducibility. The study aimed to develop a single-lead ECG algorithm incorporating the P-Delta interval (PDI) as an adjunct criterion to discriminate between right and left manifest AP. Consecutive WPW patients undergoing electrophysiological study (EPS) were retrospectively recruited and split into a derivation and validation group (1:1 ratio). Sinus rhythm ECG analysis in lead V1 was performed by three independent investigators blinded to the EPS results. Conventional ECG parameters and PDI were assessed through the global cohort. A total of 140 WPW patients were included (70 for each group). A score-based, single-lead ECG algorithm was developed through derivation analysis incorporating the PDI, R/S ratio, and QRS onset polarity in lead V1. The validation group analysis confirmed the proposed algorithm's high accuracy (95%), which was superior to the previous ones in predicting the AP side (p < 0.05). A score of ≤+1 was 96.5% accurate in predicting right AP while a score of ≥+2 was 92.5% accurate in predicting left AP. The new algorithm maintained optimal performance in specific subgroups of the global cohort showing an accuracy rate of 90%, 92%, and 96% in minimal pre-excitation, posteroseptal AP, and pediatric patients, respectively. A novel single-lead ECG algorithm incorporating the PDI interval with previous conventional criteria showed high accuracy in differentiating right from left manifest AP comprising pediatric and minimal pre-excitation subgroups in the current study.

The framing of time-dependent machine learning models improves risk estimation among young individuals with acute coronary syndromes

Acute coronary syndrome (ACS) is a common cause of death in individuals older than 55 years. Although younger individuals are less frequently seen with ACS, this clinical event has increasing incidence trends, shows high recurrence rates and triggers considerable economic burden. Young individuals with ACS (yACS) are usually underrepresented and show idiosyncratic epidemiologic features compared to older subjects. These differences may justify why available risk prediction models usually penalize yACS with higher false positive rates compared to older subjects. We hypothesized that exploring temporal framing structures such as prediction time, observation windows and subgroup-specific prediction, could improve time-dependent prediction metrics. Among individuals who have experienced ACS (nglobal_cohort = 6341 and nyACS = 2242), the predictive accuracy for adverse clinical events was optimized by using specific rules for yACS and splitting short-term and long-term prediction windows, leading to the detection of 80% of events, compared to 69% by using a rule designed for the global cohort.