Over the past decade, Programmed Death-Ligand 1 (PD-L1) has emerged as a prominent target for cancer immunotherapies. However, its potential as an immunosuppressive therapy has been limited. In this review, we present the immunological basis of graft rejection and graft-versus-host disease (GVHD), followed by a summary of biologically relevant molecular interactions of both PD-L1 and Programmed Cell Death Protein 1 (PD-1). Finally, we present a translational perspective on how PD-L1 can interrupt alloreactive-driven processes to increase immune tolerance. Unlike most current therapies that block PD-L1 and/or its interaction with PD-1, this review focuses on how upregulation or reversed sequestration of this ligand may reduce autoimmunity, ameliorate GVHD, and enhance graft survival following organ transplant.

Early coronary ischemic events are uncommon after cardiac surgery, with little known about their management or associated outcomes. We evaluated clinical outcomes of patients undergoing coronary angiography ± percutaneous coronary intervention or redo coronary artery bypass grafting for suspected coronary ischemia within 3 weeks after index cardiac surgery. This is a retrospective observational study based on data from 53,287 patients who underwent cardiac surgery at our institution (1996-2017); 180 patients (0.34%) satisfied the inclusion criteria. The primary outcome was 1-year all-cause mortality. Statistical evaluation involved χ², analysis of variance, Kaplan-Meier, and receiver operating characteristic curve analyses. Most coronary angiography ± percutaneous coronary intervention and redo coronary artery bypass grafting procedures occurred in the first 2 weeks after index cardiac surgery. Patients presenting with ST elevation myocardial infarction (STEMI)/non-STEMI had the lowest 1-year mortality (13.5%), followed by patients with ventricular tachycardia/fibrillation (28.1%), and patients with non-ventricular tachycardia/fibrillation arrest or hemodynamic instability alone the worst (38.6%) (χ² = 17.3, P = .001). Peak troponin T level after cardiac surgery was strongly predictive of 1-year mortality (area under the curve, 0.74; 95% confidence interval, 0.65-0.84; P < .001) but did not predict the presence of coronary compromise. For acute graft failure, 1-year mortality was better with percutaneous coronary intervention (18.2%) than redo coronary artery bypass grafting (23.5%) or no indicated/feasible intervention (29.2%). Although suspected myocardial ischemia requiring coronary angiography or intervention early after cardiac surgery was rare, mortality was high, particularly in presentations other than STEMI/non-STEMI. In patients with overt signs and symptoms of myocardial ischemia after index cardiac surgery, troponin T was not a reliable marker of underlying coronary or graft obstruction but was a robust predictor of 1-year mortality.

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E16514 Background: Standard-of-care for muscle-invasive bladder cancer (MIBC) consists of neoadjuvant chemotherapy (NAC) followed by radical cystectomy. The inability to noninvasively assess minimal residual disease (MRD) after NAC limits our ability to offer bladder-sparing treatment. We perform urine tumor DNA (utDNA) analysis to identify pathologic complete response (pCR) at the time of cystectomy in patients receiving NAC. Methods: We applied CAPP-Seq to urine cell-free DNA samples acquired on the day of radical cystectomy from 19 MIBC patients treated with NAC. utDNA variant-calling was performed without prior tumor mutational knowledge using a panel of 49 consensus driver genes mutated in MIBC. The utDNA level for each patient was represented by the duplex-supported non-silent driver mutation with the highest variant allele fraction (vAF) after removing germline variants. We also serially tracked utDNA variants in two patients before, during, and after NAC. Results: Comparing patients with residual disease detected in their cystectomy specimen (n = 10) to those who achieved a pCR (n = 9), median utDNA levels were 2.4% vs. 0%, respectively (P = 0.006). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD was highly correlated with the absence of pCR (P = 0.003). Analysis of two patients’ serial urine samples revealed utDNA dynamics that were consistent with treatment responses in real-time. In one patient who ultimately achieved a pCR, four non-silent driver mutations were detectable pre-NAC, including ERCC2 N238S (7.8% vAF) associated with increased chemosensitivity. One week after starting NAC, ERCC2 N238S increased by 1.6-fold in urine, as did PIK3CA E726K which increased by 8.4-fold. Four weeks post-NAC, however, all mutations previously detected in this patient’s urine became undetectable, consistent with the patient’s pCR and long-term disease-free survival. Conversely, another patient harbored two non-silent driver mutations in PLEKHS1 (1.9% vAF) and KMT2D (4.9% vAF) pre-NAC. One week after starting NAC, both mutations decreased dramatically by 8.0- and 4.3-fold, respectively. By three weeks post-NAC, however, these mutations progressively increased by 5.2-fold on average, which correlated with a lack of pCR as well as post-treatment disease progression. Two newly detected non-silent driver mutations in ARID1A and ERBB2 also emerged on NAC and persisted following completion of chemotherapy, likely reflecting the development of treatment resistance. Conclusions: utDNA MRD after NAC but before radical cystectomy for MIBC correlated significantly with pathologic response, which could help personalize patient selection for bladder-sparing treatments in the future. Serial monitoring of utDNA variants during NAC can reveal dynamic mutational changes that reflect real-time treatment responses as well as ultimate disease-free survival.

This case report presents a rare complication of a massive Type IV hiatal hernia occurring through a diaphragmatic relaxing incision (DRI) created during a previous Nissen fundoplication. An 82-year-old female presented with abdominal pain, shortness of breath, and small bowel obstruction. Imaging revealed herniation of the small bowel, colon, and spleen through a diaphragmatic defect. Seven years prior, the patient underwent a Nissen fundoplication with mesh repair, during which bilateral DRIs were created to reduce diaphragmatic tension. Despite prior concerns about operative risks, emergent surgery was performed to reduce the hernia and resect infarcted bowel. Postoperative recovery was complicated by hypotension requiring vasopressor support, but the patient ultimately recovered well. This case highlights the potential for catastrophic herniation through DRIs and underscores the need for careful surgical technique and postoperative surveillance. Literature review suggests that more focused research is needed to establish optimal management and prevention strategies for this complication.

Objective: Standard-of-care for muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. The inability to assess molecular residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. We seek to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. Methods: We applied uCAPP-Seq, a targeted next-generation sequencing method for detecting utDNA, to urine cell-free DNA samples acquired on the day of curative-intent radical cystectomy from 42 patients with non-metastatic bladder cancer, 30 of whom had a confirmed diagnosis of MIBC and 19 of whom received neoadjuvant chemotherapy. utDNA mutational calling was performed noninvasively without tumor tissue sequencing knowledge. The overall utDNA level for each patient was represented by the non-silent mutation with the highest duplex-supported variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy donors. The concordance between urine cell-free DNA and tumor tissue was determined for a subset of patients. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of mutations detected in urine cell-free DNA by applying a linear relationship derived from TCGA whole-exome sequencing of 409 MIBC tumors. Results: utDNA analysis revealed a median utDNA level of 0% in healthy donors and 2.4% in non-metastatic bladder cancer patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 87%. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (n = 26), median utDNA levels were 4.3% vs. 0%, respectively (P = 0.002). The lack of utDNA MRD detection was highly correlated with pathologic complete response by Fisher's exact test (P = 0.0001) with Youden's index-determined sensitivity of 81% and specificity of 81%. Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival compared to utDNA MRD-negative patients (HR = 7.2; P = 0.03) with a median follow-up time of 200 days. Leveraging data from TCGA, the median inferred TMB in utDNA MRD-positive patients was 198 mutations per exome. We suggest that 58% of these patients with inferred TMB ≥ this level might have been candidates for early immune checkpoint blockade. Conclusion: The lack of utDNA MRD detection prior to curative-intent radical cystectomy for muscle-invasive bladder cancer correlated significantly with pathologic complete response. utDNA MRD detection status also correlated significantly with progression-free survival. Furthermore, utDNA results can be used to noninvasively infer TMB, which may facilitate the targeted use of adjuvant immunotherapy. Citation Format: Kevin Chen, Pradeep S. Chauhan, Ramandeep K. Babbra, Wenjia Feng, Peter K. Harris, Katherine Dienstbach, Andrew Atkocius, Lenon Maguire, Faridi Qaium, Armaan Nallicheri, Brian C. Baumann, Melissa A. Reimers, Eric H. Kim, Zachary L. Smith, Vivek K. Arora, Aadel A. Chaudhuri. Urine tumor DNA MRD detection and correlation with pathologic complete response in muscle-invasive bladder cancer treated with curative-intent radical cystectomy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 547.