Spatially resolved immune exhaustion within the alloreactive microenvironment predicts liver transplant rejection.

Allograft rejection is common following clinical organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive. Calcineurin inhibitor dose escalation, corticosteroids, and/or lymphocyte depleting antibodies have remained the primary options for treatment of clinical rejection episodes. Here, we developed a highly multiplexed imaging mass cytometry panel to study the immune response in archival biopsies from 79 liver transplant (LT) recipients with either no rejection (NR), acute T cell-mediated rejection (TCMR), or chronic rejection (CR). This approach generated a spatially resolved proteomic atlas of 461,816 cells (42 phenotypes) derived from 96 pathologist-selected regions of interest. Our analysis revealed that regulatory (HLADR+ Treg) and PD1+ T cell phenotypes (CD4+ and CD8+ subsets), combined with variations in M2 macrophage polarization, were a unique signature of active TCMR. These data provide insights into the alloimmune microenvironment in clinical LT, including identification of potential targets for focused immunotherapy during rejection episodes and suggestion of a substantial role for immune exhaustion in TCMR.

Spatially resolved immune exhaustion within the alloreactive microenvironment predicts liver transplant rejection.

Allograft rejection is a frequent complication following solid organ transplantation, but defining specific immune subsets mediating alloimmunity has been elusive due to the scarcity of tissue in clinical biopsy specimens. Single cell techniques have emerged as valuable tools for studying mechanisms of disease in complex tissue microenvironments. Here, we developed a highly multiplexed imaging mass cytometry panel, single cell analysis pipeline, and semi-supervised immune cell clustering algorithm to study archival biopsy specimens from 79 liver transplant (LT) recipients with histopathological diagnoses of either no rejection (NR), acute T-cell mediated rejection (TCMR), or chronic rejection (CR). This approach generated a spatially resolved proteomic atlas of 461,816 cells derived from 98 pathologist-selected regions of interest relevant to clinical diagnosis of rejection. We identified 41 distinct cell populations (32 immune and 9 parenchymal cell phenotypes) that defined key elements of the alloimmune microenvironment (AME), identified significant cell-cell interactions, and established higher order cellular neighborhoods. Our analysis revealed that both regulatory (HLA-DR+ Treg) and exhausted T-cell phenotypes (PD1+CD4+ and PD1+CD8+ T-cells), combined with variations in M2 macrophage polarization, were a unique signature of TCMR. TCMR was further characterized by alterations in cell-to-cell interactions among both exhausted immune subsets and inflammatory populations, with expansion of a CD8 enriched cellular neighborhood comprised of Treg, exhausted T-cell subsets, proliferating CD8+ T-cells, and cytotoxic T-cells. These data enabled creation of a predictive model of clinical outcomes using a subset of cell types to differentiate TCMR from NR (AUC = 0.96 ± 0.04) and TCMR from CR (AUC = 0.96 ± 0.06) with high sensitivity and specificity. Collectively, these data provide mechanistic insights into the AME in clinical LT, including a substantial role for immune exhaustion in TCMR with identification of novel targets for more focused immunotherapy in allograft rejection. Our study also offers a conceptual framework for applying spatial proteomics to study immunological diseases in archival clinical specimens.

Examining the Role for Donor-specific Antibody Testing in Simultaneous Liver-kidney Transplantation: A Single-center Analysis of Outcomes.

BACKGROUND: Simultaneous liver-kidney transplantation (SLKT) is increasingly used for patients with concurrent end-stage liver and renal disease. Emerging evidence suggests that simultaneous liver transplant can provide a tolerogenic benefit to multiorgan transplant recipients. Posttransplant donor-specific antibody (DSA) may be associated with worse outcomes; however, the role for testing DSA in SLKT is unclear. METHODS: This study retrospectively assessed the impact of DSA on outcomes following primary SLKT at a large-volume center between 2008 and 2018. Patients were grouped by positive DSA, negative DSA, and DSA not tested, and data were obtained from our institutional database and chart review. RESULTS: The cohort included 138 SLKT recipients with a mean age of 56.1 ± 9.7 y; 61.6% were male, and 55.8% were Hispanic. Overall, 62 patients were tested for DSA posttransplant, and 33 patients (23.9%) had at least 1 DSA detected. A total of 34 patients (24.6%) experienced at least 1 episode of liver rejection, and 23 patients (16.7%) experienced kidney rejection. Over 50% of patients with de novo DSA changed status during their posttransplant course. Rates of both liver and kidney rejection were slightly higher in the DSA + group, but liver allograft, kidney allograft, and patient survival did not differ when grouped by whether DSA testing was performed or DSA positivity. CONCLUSIONS: These data demonstrate that SLKT is associated with excellent long-term patient and allograft survival with a relatively low rate of rejection. In our experience, testing for DSA does not impact SLKT outcomes' and further multicenter analyses are needed to establish standard of care.

Distinct Differences in Gastroesophageal Junction and Gastric Adenocarcinoma in 2194 Patients: In Memory of Rebecca A. Carr, February 24, 1988-January 19, 2021.

OBJECTIVE: We sought to compare gastroesophageal junction (GEJ) cancer and gastric cancer (GC) and identify clinicopathological and oncological differences. SUMMARY BACKGROUND DATA: GEJ cancer and GC are frequently studied together. Although the treatment approach for each often differs, clinico-pathological and oncological differences between the 2 have not been fully evaluated. METHODS: We retrospectively identified patients with GEJ cancer or GC who underwent R0 resection at our center between January 2000 and December 2016. Clinicopathological characteristics, disease-specific survival (DSS), and site of first recurrence were compared. RESULTS: In total, 2194 patients were analyzed: 1060 (48.3%) with GEJ cancer and 1134 (51.7%) with GC. Patients with GEJ cancer were younger (64 vs 66 years; P < 0.001), more often received neoadjuvant treatment (70.9% vs 30.2%; P < 0.001), and had lower pathological T and N status. Five-year DSS was 62.2% in patients with GEJ cancer and 74.6% in patients with GC ( P < 0.001). After adjustment for clinicopathological factors, DSS remained worse in patients with GEJ cancer (hazard ratio, 1.78; 95% confidence interval, 1.40-2.26; P < 0.001). The cumulative incidence of recurrence was approximately 10% higher in patients with GEJ cancer ( P < 0.001). The site of first recurrence was more likely to be hematogenous in patients with GEJ cancer (60.1% vs 31.4%; P < 0.001) and peritoneal in patients with GC (52.9% vs 12.5%; P < 0.001). CONCLUSIONS: GEJ adenocarcinoma is more aggressive, with a higher incidence of recurrence and worse DSS, compared with gastric adenocarcinoma. Distinct differences between GEJ cancer and GC, especially in patterns of recurrence, may affect evaluation of optimal treatment strategies.

Revisiting transplant immunology through the lens of single-cell technologies.

Solid organ transplantation (SOT) is the standard of care for end-stage organ disease. The most frequent complication of SOT involves allograft rejection, which may occur via T cell- and/or antibody-mediated mechanisms. Diagnosis of rejection in the clinical setting requires an invasive biopsy as there are currently no reliable biomarkers to detect rejection episodes. Likewise, it is virtually impossible to identify patients who exhibit operational tolerance and may be candidates for reduced or complete withdrawal of immunosuppression. Emerging single-cell technologies, including cytometry by time-of-flight (CyTOF), imaging mass cytometry, and single-cell RNA sequencing, represent a new opportunity for deep characterization of pathogenic immune populations involved in both allograft rejection and tolerance in clinical samples. These techniques enable examination of both individual cellular phenotypes and cell-to-cell interactions, ultimately providing new insights into the complex pathophysiology of allograft rejection. However, working with these large, highly dimensional datasets requires expertise in advanced data processing and analysis using computational biology techniques. Machine learning algorithms represent an optimal strategy to analyze and create predictive models using these complex datasets and will likely be essential for future clinical application of patient level results based on single-cell data. Herein, we review the existing literature on single-cell techniques in the context of SOT.

Evaluation of Fontan-associated Liver Disease and Ethnic Disparities in Long-term Survivors of the Fontan Procedure: A Population-based Study.

OBJECTIVES: Fontan-associated liver disease (FALD) has emerged as a nearly universal chronic comorbidity in patients with univentricular congenital heart disease who undergo the Fontan procedure. There is a paucity of data reporting long-term outcomes and the impact of FALD in this population. METHODS: Patients who underwent the Fontan procedure between 1992 and 2018 were identified using California registry data. Presumed FALD was assessed by a composite of liver disease codes. Primary outcomes were mortality and transplant. Multivariable regression and survival analyses were performed. RESULTS: Among 1436 patients post-Fontan, 75.9% studied were adults, with a median follow-up of 12.6 (8.4, 17.3) years. The population was 46.3% Hispanic. Overall survival at 20 years was >80%, but Hispanic patients had higher mortality risk compared with White patients [hazard ratio: 1.49 (1.09-2.03), P =0.012]. Only 225 patients (15.7%) had presumed FALD, although >54% of patients had liver disease by age 25. FALD was associated with later deaths [median: 9.6 (6.4-13.2) years post-Fontan] compared with patients who died without liver disease [4.1 (1.4-10.4) years, P =0.02]. Patients with FALD who underwent combined heart liver transplant had 100% survival at 5 years, compared with only 70.7% of patients who underwent heart transplant alone. CONCLUSIONS: In this population-based analysis of long-term outcomes post-Fontan, Hispanic ethnicity was associated with increased all-cause mortality. Further, the prevalence of FALD is underrecognized, but our data confirms that its incidence increases with age. FALD is associated with late mortality but excellent posttransplant survival. This emphasizes the need for FALD-specific liver surveillance strategies in patients post-Fontan.

Adaptation of Imaging Mass Cytometry to Explore the Single Cell Alloimmune Landscape of Liver Transplant Rejection.

Rejection continues to be an important cause of graft loss in solid organ transplantation, but deep exploration of intragraft alloimmunity has been limited by the scarcity of clinical biopsy specimens. Emerging single cell immunoprofiling technologies have shown promise in discerning mechanisms of autoimmunity and cancer immunobiology. Within these applications, Imaging Mass Cytometry (IMC) has been shown to enable highly multiplexed, single cell analysis of immune phenotypes within fixed tissue specimens. In this study, an IMC panel of 10 validated markers was developed to explore the feasibility of IMC in characterizing the immune landscape of chronic rejection (CR) in clinical tissue samples obtained from liver transplant recipients. IMC staining was highly specific and comparable to traditional immunohistochemistry. A single cell segmentation analysis pipeline was developed that enabled detailed visualization and quantification of 109,245 discrete cells, including 30,646 immune cells. Dimensionality reduction identified 11 unique immune subpopulations in CR specimens. Most immune subpopulations were increased and spatially related in CR, including two populations of CD45+/CD3+/CD8+ cytotoxic T-cells and a discrete CD68+ macrophage population, which were not observed in liver with no rejection (NR). Modeling via principal component analysis and logistic regression revealed that single cell data can be utilized to construct statistical models with high consistency (Wilcoxon Rank Sum test, p=0.000036). This study highlights the power of IMC to investigate the alloimmune microenvironment at a single cell resolution during clinical rejection episodes. Further validation of IMC has the potential to detect new biomarkers, identify therapeutic targets, and generate patient-specific predictive models of clinical outcomes in solid organ transplantation.

Treatment and outcomes of hepatocellular carcinoma in patients with Sickle cell disease: a population-based study in the U.S.

BACKGROUND: Sickle cell disease (SCD) is a rare hemoglobinopathy which can result in chronic liver disease and cirrhosis. Patients with SCD have an increased risk of hematologic malignancy, but the prevalence of hepatocellular carcinoma (HCC) in this population is unknown. Herein, the association of SCD with HCC was examined using registry data. METHODS: The SEER-Medicare database was queried to identify patients diagnosed with HCC between 2000 and 2015, and further stratified by SCD status. Propensity matching was performed to examine cancer-related survival and treatment outcomes. RESULTS: Overall 56,934 patients with HCC were identified, including 81 patients with SCD. Patients with SCD more frequently had cirrhosis [48.1% (39/81) vs 23.5% (13,377/56,853), p < 0.01] yet presented with smaller tumors [<5 cm: 51.9% (42/81) vs 38.5% (21,898/56,853), p = 0.01]. After propensity matching, SCD was not associated with attenuated survival (aHR 0.73 95%CI 0.52-1.01). When stratified by treatment, patients with SCD had equivalent outcomes to chemotherapy (p = 0.65), TACE/TARE (p = 0.35), resection (p = 0.15) and transplantation (p = 0.67) when compared to non-SCD patients. CONCLUSION: This study confirms that a subset of patients with SCD will develop HCC. Importantly, therapeutic options for HCC should not be limited by pre-existing SCD, and similar survival should be expected when compared to non-SCD patients.

Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization.

BACKGROUND: Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. METHODS: Children (≤18 years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. RESULTS: A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p = 0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p = 0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. CONCLUSIONS: These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation.

Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gamma-glutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.

Living Donor Versus Deceased Donor Pediatric Liver Transplantation: A Systematic Review and Meta-analysis.

Reduced-size deceased donors and living donor liver transplantation (LDLT) can address the organ shortage for pediatric liver transplant candidates, but concerns regarding technical challenges and the risk of complications using these grafts have been raised. The aim of this study was to compare outcomes for pediatric LDLT and deceased donor liver transplantation (DDLT) via systematic review. METHODS: A systematic literature search was performed to identify studies reporting outcomes of pediatric (<18 y) LDLT and DDLT published between 2005 and 2019. A meta-analysis was conducted to examine peri- and postoperative outcomes using fixed- and random-effects models. RESULTS: Overall, 2518 abstracts were screened, and 10 studies met criteria for inclusion. In total, 1622 LDLT and 6326 DDLT pediatric patients from 4 continents were examined. LDLT resulted in superior patient survival when compared with DDLT at 1, 3, and 5 y post-LT (1-y hazard ratio: 0.58, 95% confidence interval [CI] 0.47-0.73, P < 0.0001). Similarly, LDLT resulted in superior graft survival at all time points post-LT when compared with DDLT (1-y hazard ratio: 0.56 [95% CI 0.46-0.68], P < 0.0001]. The OR for vascular complications was 0.73 (95% CI 0.39-1.39) and 1.31 (95% CI 0.92-1.86) for biliary complications in LDLT compared with DDLT, whereas LDLT was associated with lower rates of rejection (OR: 0.66 [95% CI 0.45-0.96], P = 0.03). CONCLUSIONS: This meta-analysis demonstrates that LDLT may offer many advantages when compared with DDLT in children and suggests that LDLT should continue to be expanded to optimize outcomes for pediatric LT candidates.

Creation of a Single Cell RNASeq Meta-Atlas to Define Human Liver Immune Homeostasis.

The liver is unique in both its ability to maintain immune homeostasis and in its potential for immune tolerance following solid organ transplantation. Single-cell RNA sequencing (scRNA seq) is a powerful approach to generate highly dimensional transcriptome data to understand cellular phenotypes. However, when scRNA data is produced by different groups, with different data models, different standards, and samples processed in different ways, it can be challenging to draw meaningful conclusions from the aggregated data. The goal of this study was to establish a method to combine 'human liver' scRNA seq datasets by 1) characterizing the heterogeneity between studies and 2) using the meta-atlas to define the dominant phenotypes across immune cell subpopulations in healthy human liver. Publicly available scRNA seq data generated from liver samples obtained from a combined total of 17 patients and ~32,000 cells were analyzed. Liver-specific immune cells (CD45+) were extracted from each dataset, and immune cell subpopulations (myeloid cells, NK and T cells, plasma cells, and B cells) were examined using dimensionality reduction (UMAP), differential gene expression, and ingenuity pathway analysis. All datasets co-clustered, but cell proportions differed between studies. Gene expression correlation demonstrated similarity across all studies, and canonical pathways that differed between datasets were related to cell stress and oxidative phosphorylation rather than immune-related function. Next, a meta-atlas was generated via data integration and compared against PBMC data to define gene signatures for each hepatic immune subpopulation. This analysis defined key features of hepatic immune homeostasis, with decreased expression across immunologic pathways and enhancement of pathways involved with cell death. This method for meta-analysis of scRNA seq data provides a novel approach to broadly define the features of human liver immune homeostasis. Specific pathways and cellular phenotypes described in this human liver immune meta-atlas provide a critical reference point for further study of immune mediated disease processes within the liver.

Surgical shunts for extrahepatic portal vein obstruction in pediatric patients: a systematic review.

BACKGROUND: Extrahepatic portal vein obstruction (EHPVO) causes portal hypertension in noncirrhotic children. Among surgical treatments, it is unclear whether the meso-Rex shunt (MRS) or portosystemic shunt (PSS) offers lower post-operative morbidity and superior patency over time. Our objective was to evaluate long-term outcomes comparing MRS and PSS for pediatric patients with EHPVO. METHODS: A systematic review was conducted of articles reporting children undergoing surgical shunts for EHPVO from 1/2000-2/2020. Of 87 articles screened, 22 were eligible for inclusion. The primary outcome was shunt thrombosis and secondary outcomes included non-operative complications, stenosis, and re-operation. RESULTS: Eighteen of 22 studies were of good quality and four had fair quality. Of 461 patients included, 340 underwent MRS and 121 underwent PSS. MRS were associated with a higher rate of post-operative thrombosis when compared to PSS (14.1% vs 5.8%, p = 0.021). There were 40/340 MRS patients (11.8%) that required at least one re-operation for either shunt thrombosis or stenosis, versus 5/121 PSS patients (4.1%), p = 0.019. CONCLUSION: Both MRS and PSS result in acceptable long-term patency rates, but the more technically demanding MRS is associated with higher post-shunt thrombosis, often requiring further operative intervention. This study suggests that PSS may offer advantages for pediatric patients with EHPVO.

Meta-analysis and meta-regression of outcomes for adult living donor liver transplantation versus deceased donor liver transplantation.

Prior single center or registry studies have shown that living donor liver transplantation (LDLT) decreases waitlist mortality and offers superior patient survival over deceased donor liver transplantation (DDLT). The aim of this study was to compare outcomes for adult LDLT and DDLT via systematic review. A meta-analysis was conducted to examine patient survival and graft survival, MELD, waiting time, technical complications, and postoperative infections. Out of 8600 abstracts, 19 international studies comparing adult LDLT and DDLT published between 1/2005 and 12/2017 were included. U.S. outcomes were analyzed using registry data. Overall, 4571 LDLT and 66,826 DDLT patients were examined. LDLT was associated with lower mortality at 1, 3, and 5 years posttransplant (5-year HR 0.87 [95% CI 0.81-0.93], p < .0001), similar graft survival, lower MELD at transplant (p < .04), shorter waiting time (p < .0001), and lower risk of rejection (p = .02), with a higher risk of biliary complications (OR 2.14, p < .0001). No differences were observed in rates of hepatic artery thrombosis. In meta-regression analysis, MELD difference was significantly associated with posttransplant survival (R2 0.56, p = .02). In conclusion, LDLT is associated with improved patient survival, less waiting time, and lower MELD at LT, despite posing a higher risk of biliary complications that did not affect survival posttransplant.

How Many Nodes Need to be Removed to Make Esophagectomy an Adequate Cancer Operation, and Does the Number Change When a Patient has Chemoradiotherapy Before Surgery?

INTRODUCTION AND DESIGN: Node dissection during esophagectomy is an important aspect of esophageal cancer staging. Controversy remains as to how many nodes need to be resected in order to properly stage a patient and whether the removal of more nodes carries a stage-independent survival benefit. A review of the literature performed by a group of experts in the subject may help define a minimum accepted number of lymph nodes to be resected in both primary surgery and post-induction therapy scenarios. RESULTS AND CONCLUSIONS: The existing evidence generally supports the goal of obtaining a minimum of 15 lymph nodes for pathological examination in both primary surgery and post-induction therapy scenarios.

Incidence and Risk Factors for Isolated Esophageal Cancer Recurrence to the Brain.

BACKGROUND: Recurrence of esophageal cancer in the brain is rare but associated with a poor prognosis. Identification of risk factors for isolated brain metastasis of esophageal cancer (iBMEC) after surgical treatment may guide surveillance recommendations to enable early identification and intervention before widespread metastasis. METHODS: Patients with iBMEC (n = 38) were identified from a prospective database of patients with esophageal cancer who underwent esophagectomy. Risk factors for iBMEC were identified using competing risk regression analysis. RESULTS: In a cohort of 1760 patients, 39% recurred and iBMEC developed in 2% by the end of the study. Survival in patients with iBMEC was similar to survival in patients with distant recurrence (median overall survival, 0.95 years; 95% confidence interval, 0.6-1.5 years). More than half of patients with iBMEC were diagnosed within 1 year postoperatively. All 38 patients with iBMEC had received neoadjuvant therapy before surgery. Pathologic complete response (PCR) to neoadjuvant therapy was associated with improved survival after brain recurrence (median overall survival, 1.56 vs 0.66 years; P = .019). CONCLUSIONS: In patients with PCR, iBMEC may represent true isolated recurrence, whereas in those with residual nodal disease, iBMEC may actually be the first observed site of widespread metastasis. Patients who receive neoadjuvant therapy, especially with PCR, may benefit from brain imaging, both preoperatively and with routine surveillance.

Surveillance Implications of Recurrence Patterns in Early Node-Negative Esophageal Adenocarcinoma.

BACKGROUND: There are limited data regarding optimal surveillance after curative resection for esophageal cancer. Once disease recurrence is diagnosed, the prognosis is poor. The purpose of this article was to characterize disease recurrence in patients with early esophageal adenocarcinoma. METHODS: Two hundred sixty patients were identified from a prospective institutional database with pathologic T1 and T2 node-negative disease therapy treated with curative esophagectomy alone for esophageal adenocarcinoma between 1995 and 2017. Competing risk analysis was used to analyze factors associated with recurrence. RESULTS: The 5-year cumulative incidence of recurrence was 12%. Predictive factors for increased risk of recurrence included increasing tumor size, poor differentiation, and pathologic T2 disease (P < .05), whereas presence of Barrett's esophagus on pathology was protective. Recurrence within 2 years was 2.5%, 6.1%, and 12% for T1a, T1b, and T2 disease, respectively. At 5 years cumulative incidence of recurrence was 8.2%, 11.5% and 22.2%, respectively. Median overall survival after recurrence was 1.04 years (95% confidence interval, 0.7-2.4). There were 14 subclinical and 13 symptomatic recurrences; patients with symptomatic recurrence had a significantly shorter overall survival after recurrence occurred (0.31 vs 0.71 years, P = .018). CONCLUSIONS: Among early node-negative patients with esophageal cancer undergoing curative resection, 5-year recurrence was 12%. Survival after recurrence was poor, and only a few patients had isolated locoregional recurrence at time of diagnosis, suggesting that scheduled surveillance may have an important role.

Ongoing Challenges with Clinical Assessment of Nodal Status in T1 Esophageal Adenocarcinoma.

BACKGROUND: Endoscopic mucosal resection (EMR) has emerged as an esophageal-preserving treatment for T1 esophageal adenocarcinoma (EAC); however, only patients with negligible risk of lymph node metastasis (LNM) are eligible. Reliable clinical diagnostic tools for LNM are lacking, as such, several risk assessment scores have been developed. The purpose of this study was to externally validate 2 previously published risk scores (Lee and Weksler) for clinical prediction of LNM in T1 EAC patients. METHODS: In adherence with the Lee and Weksler scores, esophagectomy patients with pathologic T1 EAC were identified. Sub-analysis was performed in patients with clinical T1 based on EMR. Predictive accuracy of the scores was evaluated by calculating the area under the curve of the receiver operating characteristic curve and calibration plots. The areas under the curves were compared using Venkatraman's test for paired receiver operating characteristic curves. RESULTS: Of 233 patients identified who met study criteria for external validation, 3 T1a and 32 T1b patients had LNM. The receiver operating characteristic curves demonstrated comparable high predictive and discriminatory capabilities with areas under the curves of 0.832 and 0.824 for the Lee and Weksler scores, respectively (p = 0.750). Results were more variable for the EMR cohort. Based on the risk thresholds defined by each score, the false-positive rate compared against the pathologic LNM status were 73% and 56% for Lee and Weksler, with 3% false negatives in the latter. On EMR, the false-positive rates were 70% and 50% for Lee and Weksler, with no false negatives. CONCLUSIONS: Both scoring systems demonstrated good discriminatory ability and predictive accuracy for LNM, but the defined thresholds resulted in a high false-positive rate. A better scoring system based on clinical characteristics is needed to better identify patients with local disease.

Patterns and risk of recurrence in patients with esophageal cancer with a pathologic complete response after chemoradiotherapy followed by surgery.

OBJECTIVES: A pathologic complete response in patients with locally advanced esophageal cancer after chemoradiotherapy and surgery is associated with improved overall and disease-free survival. Nevertheless, approximately one third of patients with a pathologic complete response still have a recurrence. The aim of this study was to evaluate risk factors and patterns of recurrence in patients with locally advanced esophageal cancer who achieved a pathologic complete response after chemoradiotherapy and surgery. METHODS: We performed a retrospective review of a single-institution database of 233 patients with stage II and III esophageal cancer with a pathologic complete response after chemoradiotherapy and surgery between 1997 and 2017. A multivariable competing risk-regression model was used to identify predictors of recurrence. RESULTS: A total of 61 patients exhibited recurrence in this cohort, 43 with adenocarcinoma and 18 with squamous cell carcinoma. Five-year cumulative incidence of recurrence did not vary by histology. Univariable analysis revealed that poor tumor differentiation (hazard ratio, 2.28; P = .022) and advanced clinical stage (hazard ratio, 1.89; P = .042) are predictors of recurrence in the esophageal adenocarcinoma subgroup, whereas poor tumor differentiation remained the only independent predictor on multivariable analysis in the entire cohort (hazard ratio, 2.28; P = .009). Patients with esophageal adenocarcinoma had a higher incidence of distant recurrences, and patients with esophageal squamous cell carcinoma demonstrated a higher incidence of loco-regional recurrence (P = .039). CONCLUSIONS: Poor tumor differentiation is an independent risk factor for recurrence in patients with esophageal cancer with a pathologic complete response. Although there is no difference in the cumulative incidence of recurrence between esophageal adenocarcinoma and esophageal squamous cell carcinoma, patterns of recurrence appear to differ. Thus, treatment and surveillance strategies may be tailored appropriately.