Survival In Esophageal Adenocarcinoma Research Articles

Hexokinase 2 as an independent risk factor for worse patient survival in esophageal adenocarcinoma and as a potential therapeutic target protein: A retrospective, single‑center cohort study.

Cancer cells exhibit a distinct metabolic profile that features an upregulation of less efficient glycolysis accompanied by lactate production for energy generation, in contract to the characteristic metabolism of normal cells. Consequently, cancer research has focused on the enzymes that participate in these cancer metabolic pathways. Among them, hexokinase 2 (HK2) has an important position as the initial enzyme in the glycolytic pathway. Increased expression levels of HK2 have been correlated with an increased risk of poor patient outcomes and advanced tumor stages in a number of malignant tumors, such as gastric carcinoma. The present study aimed to investigate the specific role of HK2 in patients diagnosed with esophageal adenocarcinoma. A total of 643 patients with esophageal adenocarcinoma were included. Immunohistochemical staining and HK2 mRNA in situ probes were used to investigate the association of HK2 expression levels with clinical and molecular tumor characteristics. Patients who exhibited high HK2 expression levels demonstrated significantly reduced overall survival (OS) times compared with patients who exhibited low HK2 expression levels (29.6 vs. 39.9 months, respectively; P=0.027). Furthermore, high HK2 expression levels were demonstrated to be an independent risk factor for reduced patient survival (hazard ratio, 1.65; 95% CI, 1.09-2.50; P=0.018). Significantly reduced patient survival was also demonstrated in the subgroups of male patients, patients with primarily resected tumors, patients with HER2-negative tumors and patients with tumors exhibiting Y chromosome loss. Elevated expression of HK2 was identified as a risk factor for unfavorable patient survival in esophageal adenocarcinoma. This revelation suggests the potential for future diagnostic and therapeutic avenues tailored to this specific patient subset. Identifying patients with high HK2 expression may pinpoint a higher-risk cohort, paving the way for comprehensive prospective studies that could advocate for intensified monitoring and more aggressive therapeutic regimens. Furthermore, the targeted inhibition of HK2 could hold promise as a strategy to potentially enhance patient outcomes.

Disparities in esophageal cancer incidence and esophageal adenocarcinoma mortality in the United States over the last 25-40 years.

Esophageal carcinoma presents as 2 types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) with the frequency of both changing in the United States (US). To investigate EAC/ESCC incidence time trends among the 3 main US racial groups and investigate trends in US EAC survival by ethnicity. Twenty-five years (1992-2016) of data from SEER 13 program was analyzed to compare incidence trends in EAC and ESCC between non-Hispanic whites (nHW), non-Hispanic Blacks (nHB) and Hispanics (Hisp) using SEERStat®. In addition, SEER 18 data, from 1975-2015, on EAC in the US was analyzed to evaluate racial disparities in incidence and survival using SEERStat® and Ederer II method. In the 3 major US ethnic groups, age-adjusted incidence of ESCC has declined while EAC has continued to rise from 1992-2016. Of note, in Hisp, the EAC incidence rate increased while ESCC decreased from 1992 to 2016, resulting in EAC as the predominant esophageal cancer subtype in this group since 2011, joining nHW. Furthermore, although ESCC remains the predominant tumor in nHB, the difference between ESCC and EAC has narrowed dramatically over 25 years. EAC survival probabilities were worse in all minority groups compared to nHw. Hisp have joined nHW as US ethnic groups more likely to have EAC than ESCC. Of note, EAC incidence in nHB is increasing at the highest rate nationally. Despite lower EAC incidence in all minority groups compared to nHW, these populations have decreased survival compared to nHW.

ANPEP/CD13 Expression as a Marker of Lymphovascular Invasion and Survival in Esophageal Adenocarcinoma

BackgroundThe presence of lymphovascular invasion (LVI) in early esophageal adenocarcinoma (EAC) is associated with more aggressive disease. Molecular markers associated with LVI are still largely unknown. Using a combination of transcriptomic analysis and validation experiments, we sought to describe markers for LVI and survival. MethodsWe performed NanoString expression profiling using RNA from 60 EAC specimens collected from surgery-only cases between 2000 and 2012. Differentially expressed genes (DEGs) were correlated with pathologic characteristics (T and N status and presence of LVI). Kaplan-Meier and Cox regression analyses were used to correlate gene expression with overall survival. Expression of alanyl aminopeptidase, membrane (ANPEP)/CD13 was validated by immunohistochemistry (IHC) in EAC tissue microarray and in EAC cell lines. ResultsWe identified >20 up-regulated DEGs in tumor samples containing LVI. Multivariable analysis showed depth of invasion and ANPEP/CD13 expression were independently associated with overall survival, whereas nodal status was not. IHC analysis demonstrated overexpression of the ANPEP/CD13 protein in dysplastic Barrett esophagus and EAC tumors. Kaplan-Meier analysis showed that patients with higher RNA expression and strongly positive ANPEP/CD13 membrane IHC-Histoscore staining have shorter survival (P = .002). Down-regulation of ANPEP/CD13 expression by short hairpin RNA vector reduces colony formation, migration, and invasion of FLO-1 EAC cells. Overexpression of CD13 in SKGT4 EAC cells increases colony formation, motility, and invasion in vitro. ConclusionsElevated expression of ANPEP/CD13 indicates shorter survival of EAC patients and a more invasive phenotype of cancer cells in vitro. Validation in a larger sample group is required to better understand the clinical significance of ANPEP/CD13 and other candidate genes.

Esophageal Cancer-Derived Organoids to Predict Patients' Treatment Response

The absolute 10-year overall survival of esophageal adenocarcinoma (EAC) has significantly increased from 26% to 36% due to neoadjuvant chemoradiotherapy (nCRT) with consecutive radical resection. However, 20-25% of EAC patients don't respond to nCRT and need alternative treatment, and 20-30% have a complete pathological response and may not need resection. Therefore, there is an urgent need for better models to accurately predict response of EAC to nCRT. Accumulating evidence indicates that patient-derived organoids (PDOs) may predict treatment responses, but the ability of PDOs to predict responses to chemoradiation in EAC patients remains unknown. Hence, we generated patient derived EAC cancer organoids (ec-PDOs) to examine their response to nCRT. The biopsies from treatment-naïve EAC patients after informed consent were used to establish ec-PDOs. Next, we investigated the response of ec-PDOs to the components of standard-of-care neoadjuvant treatment, including irradiation, carboplatin, and paclitaxel. Finally, the potential of ec-PDOs to reflect patients' response to nCRT before esophageal resection was evaluated. Mechanically and enzymatically dispersed patient derived EAC biopsies were cultured as ec-PDOs for up to 10 passages, indicating the self-renewal and expansion potential. These ec-PDOs expressed the EAC marker MUC5AC, indicating the EAC origin. Differences in growth kinetics and response to irradiation, carboplatin, and paclitaxel were observed between patients specific ec-PDOs. However, similar dose-response curves were seen within ec-PDOs from the same patient after different passages. This indicates that ec-PDOs exhibit interpatient response heterogeneity but have good reproducible responses within the same patient. Moreover, after combined treatment with irradiation (IR), carboplatin (Car), and paclitaxel (Pac) to mimic nCRT in EAC patients, the stem cell survival of ec-PDOs from patients with complete response (CR) and partial response (PR) are lower than that from those with progressive disease (PD). The preliminary findings in this study suggest a great potential of ec-PDOs to predict patient-specific responses to neoadjuvant treatment in EAC patients.

High NANOG expression correlates with worse patients’ survival in esophageal adenocarcinoma

BackgroundPatients diagnosed with esophageal cancer demonstrate a low overall survival even despite the established multimodal therapy as the current standard of care. Therefore, further biomarkers for patients with high-risk and additional therapy options are needed. NANOG is a transcription factor, which can be found in stem cells and is known to support tumorigenesis.MethodsSix hundred sixty patients with esophageal adenocarcinoma, who were operated at the University of Cologne with a curative intent, were included. Immunohistochemical stainings for NANOG were performed. The study population was divided into NANOG-positive and -negative subgroups.ResultsPositive NANOG expression correlates significantly with worse overall survival (p = 0.002) and could be confirmed as an independent risk factor for worse patient survival in multivariate analysis (HR = 1.40, 95%CI = 1.09–1.80, p = 0.006). This effect could be detected in the subgroup of primarily operated patients, but not in patients after neoadjuvant therapy.ConclusionsWe describe a NANOG-positive subgroup of patients with esophageal cancer, who exhibit worse overall survival in a large patient cohort. This discovery suggests the potential use of NANOG as a biomarker for both intensified therapy and stricter follow-up regimes. Additionally, NANOG-positive stem cell-like cancer cells could be used as a new antitumoral treatment target if validated in mechanistic and clinical studies.

Correlations between Molecular Alterations, Histopathological Characteristics, and Poor Prognosis in Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is a severe malignancy with increasing incidence, poorly understood pathogenesis, and low survival rates. We sequenced 164 EAC samples of naïve patients (without chemo-radiotherapy) with high coverage using next-generation sequencing technologies. A total of 337 variants were identified across the whole cohort, with TP53 as the most frequently altered gene (67.27%). Missense mutations in TP53 correlated with worse cancer-specific survival (log-rank p = 0.001). In seven cases, we found disruptive mutations in HNF1alpha associated with other gene alterations. Moreover, we detected gene fusions through massive parallel sequencing of RNA, indicating that it is not a rare event in EAC. In conclusion, we report that a specific type of TP53 mutation (missense changes) negatively affected cancer-specific survival in EAC. HNF1alpha was identified as a new EAC-mutated gene.

An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers.

Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression. Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations. By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy. Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types. Swedish Cancer Society, Lions Cancer Foundation, Selanders Foundation, P.O. Zetterling Foundation, U-CAN supported by SRA CancerUU, Uppsala University and Region Uppsala.

Predictive value of Mandard score and nodal status on recurrence patterns and survival of esophageal adenocarcinoma after neoadjuvant therapy and surgery

Predictive value of Mandard score and nodal status on recurrence patterns and survival of esophageal adenocarcinoma after neoadjuvant therapy and surgery

Value of a 18F-FDG PET/CT Semi-quantitative Parameter (SUVmax) in Predicting the Survival of Patients with Esophageal Cancer Subtypes

Background: Flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan is employed for initial staging and restaging of esophageal cancer patients. Objectives: The present study aimed to assess the value of a semi-quantitative parameter of 18F-FDG PET/CT scan, that is, maximum standardized uptake value (SUVmax), to determine its correlation with patient survival in two subtypes of esophageal cancer, including squamous cell carcinoma (SCC) and adenocarcinoma. Patients and Methods: This cross-sectional study was performed on patients with esophageal SCC and adenocarcinoma, undergoing 18F-FDG PET/CT scan for initial staging before any treatment. The 18F-FDG PET/CT semi-quantitative parameter (SUVmax) was determined by reviewing the PET/CT images. The patients were reevaluated using 18F-FDG PET/CT scan for restaging within 12 - 24 months. Results: No significant difference was observed in the SUVmax values of the primary tumor, metastatic lymph nodes, or distant metastasis between the adenocarcinoma and SCC groups, regardless of response to treatment. Similarly, no significant association was found between the short-term survival of patients with adenocarcinoma and the SUVmax values of the primary tumor, metastatic lymph nodes, or distant metastasis. Based on the survival curve, one- and two-year survival rates were estimated at 75% and 63.9% in patients with SCC and at 80% and 60% in patients with adenocarcinoma, respectively. In the SCC group, a significantly higher SUVmax was detected in deceased patients with distant metastatic lesions compared to cancer survivors. According to the area under the ROC curve, the SUVmax of metastatic lesions showed high potential for predicting the mortality of SCC patients. Conclusion: The assessment of SUVmax in distant metastatic lesions by 18F-FDG-PET/CT may help predict the survival of patients with esophageal SCC. However, 18F-FDG-PET/CT findings were not associated with the survival of esophageal adenocarcinoma; therefore, further evaluations on a larger sample size and a longer follow-up are required.

RAD51 Is Implicated in DNA Damage, Chemoresistance and Immune Dysregulation in Solid Tumors.

In normal cells, homologous recombination (HR) is tightly regulated and plays an important role in the maintenance of genomic integrity and stability through precise repair of DNA damage. RAD51 is a recombinase that mediates homologous base pairing and strand exchange during DNA repair by HR. Our previous data in multiple myeloma and esophageal adenocarcinoma (EAC) show that dysregulated HR mediates genomic instability. Purpose of this study was to investigate role of HR in genomic instability, chemoresistance and immune dysregulation in solid tumors including colon and breast cancers. The GEO dataset were used to investigate correlation of RAD51 expression with patient survival and expression of various immune markers in EAC, breast and colorectal cancers. RAD51 was inhibited in cancer cell lines using shRNAs and a small molecule inhibitor. HR activity was evaluated using a plasmid-based assay, DNA breaks assessed by evaluating expression of γ-H2AX (a marker of DNA breaks) and p-RPA32 (a marker of DNA end resection) using Western blotting. Genomic instability was monitored by investigating micronuclei (a marker of genomic instability). Impact of RAD51 inhibitor and/or a DNA-damaging agent was assessed on viability and apoptosis in EAC, breast and colon cancer cell lines in vitro and in a subcutaneous tumor model of EAC. Impact of RAD51 inhibitor on expression profile was monitored by RNA sequencing. Elevated RAD51 expression correlated with poor survival of EAC, breast and colon cancer patients. RAD51 knockdown in cancer cell lines inhibited DNA end resection and strand exchange activity (key steps in the initiation of HR) as well as spontaneous DNA breaks, whereas its overexpression increased DNA breaks and genomic instability. Treatment of EAC, colon and breast cancer cell lines with a small molecule inhibitor of RAD51 inhibited DNA breaking agent-induced DNA breaks and genomic instability. RAD51 inhibitor potentiated cytotoxicity of DNA breaking agent in all cancer cell types tested in vitro as well as in a subcutaneous model of EAC. Evaluation by RNA sequencing demonstrated that DNA repair and cell cycle related pathways were induced by DNA breaking agent whereas their induction either prevented or reversed by RAD51 inhibitor. In addition, immune-related pathways such as PD-1 and Interferon Signaling were also induced by DNA breaking agent whereas their induction prevented by RAD51 inhibitor. Consistent with these observations, elevated RAD51 expression also correlated with that of genes involved in inflammation and other immune surveillance. Elevated expression of RAD51 and associated HR activity is involved in spontaneous and DNA damaging agent-induced DNA breaks and genomic instability thus contributing to chemoresistance, immune dysregulation and poor prognosis in cancer. Therefore, inhibitors of RAD51 have great potential as therapeutic agents for EAC, colon, breast and probably other solid tumors.

AXL Promotes Metformin-Induced Apoptosis Through Mediation of Autophagy by Activating ROS-AMPK-ULK1 Signaling in Human Esophageal Adenocarcinoma.

AXL receptor tyrosine kinase promotes an invasive phenotype and chemotherapy resistance in esophageal adenocarcinoma (EAC). AXL has been implicated in the regulation of autophagy, but the underlying molecular mechanism remains poorly understood. Herein, we investigate the mechanistic role of AXL in autophagy as well as metformin-induced effects on the growth and survival of EAC. We demonstrate that AXL mediates autophagic flux through activation of AMPK-ULK1 signaling in a reactive oxygen species (ROS)-dependent mechanism by glucose starvation. AXL positively regulates basal cellular ROS levels without significantly affecting mitochondrial ROS production in EAC cells. Pharmacological inhibition of cellular ROS using Trolox abrogates glucose starvation-induced AMPK signaling and autophagy. We demonstrate that AXL expression is required for metformin-induced apoptosis in EAC cells in vitro. The apoptosis induction by metformin is markedly attenuated by inhibition of autophagy through genetic silencing of Beclin1 or ATG7 autophagy mediators, thereby confirming the requirement of intact autophagy for enhancing metformin-induced apoptosis in EAC cells. Our data indicate that metformin-induced autophagy displays a pro-apoptotic function in EAC cells. We show that the metformin-induced suppression of tumor growth in vivo is highly dependent on AXL expression in a tumor xenograft mouse model of EAC. We demonstrate that AXL promotes metformin-induced apoptosis through activation of autophagy in EAC. AXL may be a valuable biomarker to identify tumors that are sensitive to metformin. Therefore, AXL expression could inform the selection of patients for future clinical trials to evaluate the therapeutic efficacy of metformin in EAC.

Esophageal adenocarcinoma phenotypes and risk factors

The incidence of esophageal adenocarcinoma (EAC) has increased significantly over the last several decades. The majority of EAC patients present without a prior history of Barrett's esophagus (BE). As a result, endoscopic surveillance has made a suboptimal impact on EAC survival. These concerns raise serious question whether the time has come to take a different direction. The aim of this article is to review evolving evidence of EAC phenotypes and risk factors. A recent study has identified two phenotypes of EAC based on the presence or absence of intestinal metaplasia (IM) in the background of the tumor (BE/IM and non-BE/IM). The study found that one-half of patients with EAC have the non-BE/IM phenotype, which is associated with more aggressive behavior and worse survival. A retrospective review demonstrates that the proportion of the two phenotypes has been stable over the last decades. Similarly, the increasing incidence of EAC cannot be explained by an increased frequency of new, unique risk factors but rather by a higher prevalence of already known risk factors. Emerging data also demonstrates that, whereas reflux symptoms are an unreliable feature for screening regardless of phenotype, the absence of reflux symptoms is more common for the non-BE/IM. Differences in the degree of genomic methylation and immune response might explain the two phenotypes at a genomic level. EAC phenotypes have implications for tumor behavior and phenotypic differences might underlie our suboptimal screening efforts. Future screening efforts should not uniformly rely on reflux symptoms as a prerequisite for screening and should consider alternatives to the current screening strategy.

Systematic review and validation of clinical models predicting survival after oesophagectomy for adenocarcinoma.

Oesophageal adenocarcinoma poses a significant global health burden, yet the staging used to predict survival has limited ability to stratify patients by outcome. This study aimed to identify published clinical models that predict survival in oesophageal adenocarcinoma and to evaluate them using an independent international multicentre dataset. A systematic literature search (title and abstract) using the Ovid Embase and MEDLINE databases (from 1947 to 11 July 2020) was performed. Inclusion criteria were studies that developed or validated a clinical prognostication model to predict either overall or disease-specific survival in patients with oesophageal adenocarcinoma undergoing surgical treatment with curative intent. Published models were validated using an independent dataset of 2450 patients who underwent oesophagectomy for oesophageal adenocarcinoma with curative intent. Seventeen articles were eligible for inclusion in the study. Eleven models were suitable for testing in the independent validation dataset and nine of these were able to stratify patients successfully into groups with significantly different survival outcomes. Area under the receiver operating characteristic curves for individual survival prediction models ranged from 0.658 to 0.705, suggesting poor-to-fair accuracy. This study highlights the need to concentrate on robust methodologies and improved, independent, validation, to increase the likelihood of clinical adoption of survival predictions models.

Lymphadenectomy and Survival in Esophageal Adenocarcinoma - A Systematic Review and Meta-Analysis

Background: Controversy has been reported concerning the extent of lymphadenectomy during esophageal adenocarcinoma (EAC) resection surgery in the era of multimodal therapy. Due to unfavorable biology, there is potential for the neoplasia to persist after neoadjuvant therapy. Extended lymphadenectomy might bring a survival advantage to these patients. This systematic review and meta-analysis evaluates whether the extension of lymphadenectomy has impact on overall survival (OS) in patients with EAC submitted to esophagectomy preceded by neoadjuvant therapy.

Impact of neoadjuvant chemotherapy on nodal regression and survival in oesophageal adenocarcinoma

BackgroundThe prognostic value of lymph node regression (LNR) following neoadjuvant chemotherapy (nCT) for oesophageal and gastro-oeosphageal adenocarcinoma remains unclear. This study aimed to characterise the long-term survival outcomes of LNR in patients having resectional surgery after nCT. MethodsThis study included patients undergoing oesophagectomy or extended total gastrectomy for oesophageal and junctional tumours (Siewert types 1,2,3) at the Queen Elizabeth Hospital Birmingham from 2012 to 2018. Lymph nodes retrieved at surgery were examined for evidence of a response to chemotherapy. Patients were classified as lymph node-negative (either negative nodes with no evidence of previous tumour involvement or negative with evidence of complete regression) or positive with either partial or no response. ResultsThis study identified 183 patients who received nCT, of which 71% (130/183) had positive lymph nodes. Of these 130 patients, 44% (57/130) had a lymph node response and 56% (73/130) did not. The remaining 53 patients (29.0%) had negative lymph nodes with no evidence of tumour. Lymph node responders had a significant survival benefit compared to patients without lymph node response, but shorter than those with negative lymph nodes (median: 27 vs 18 vs NR months, p < 0·001). On multivariable analysis, lymph node responders had an improved overall (Hazard ratio (HR): 0.86, 95% CI: 0.80–0.92, p < 0.001) and recurrence-free (HR: 0.90, 95% CI: 0.82–0.98, p = 0.030) survival. ConclusionLymph node regression is an important prognostic factor, warranting closer evaluation over primary tumour response to help with planning further adjuvant therapy in these patients.

C-Reactive Protein and C-Reactive Protein-Based Scores to Predict Survival in Esophageal and Junctional Adenocarcinoma: Systematic Review and Meta-Analysis.

Esophageal adenocarcinoma (EAC) has a poor prognosis; predictive markers of prognosis would facilitate advances in personalized therapy. C-reactive protein (CRP) and CRP-based scores are increasingly recommended across oncology; however, their role and value in EAC is unclear. This systematic review and meta-analysis examined CRP cut-point and scores and how they may best be applied in predicting survival in EAC. A systematic literature search was conducted in EMBASE, Medline, Web of Science, Cochrane, Scopus and CINAHL databases, from inception to 1st October 2020. Studies reporting data from adults with EAC including adenocarcinoma of the gastro-esophageal junction (AEG), pre-treatment CRP or CRP-based score and Hazard Ratio (HR) for survival were included. QUIPS tool assessed risk of bias. Meta-analysis was undertaken. A total of 819 records were screened. Eight papers were included, with data for 1475 people. CRP cut-points ranged from 2.8 to 10 mg/L. The Glasgow Prognostic Score (GPS) and modified GPS were the most commonly reported scores. On meta-analysis, elevated preoperative GPS/mGPS was significantly associated with worse overall survival (hazards ratio [HR] 1.81, 95% confidence interval [CI] 1.25-2.62, p = 0.002); results were similar in subgroup analyses of multimodal treatment, M0 disease, and R0 resection. This is the first review to evaluate comprehensively the evidence for CRP and CRP-based scores in EAC. Meta-analysis demonstrated that elevated preoperative GPS or mGPS was significantly associated with reduced overall survival in EAC, including AEG. There is insufficient evidence to support use of CRP alone. Future studies should examine GPS/mGPS in EAC prospectively, alone and combined with other prognostic markers.

267 INTESTINAL STEM CELL MARKERS AND ITS POTENTIAL USE IN THE CLINICOPATHOLOGICAL SETTING OF ESOPHAGEAL ADENOCARCINOMA

Abstract Barrett’s esophagus (BE) is the primary precursor lesion of esophageal adenocarcinoma (EAC), which not only resembles the intestinal mucosa morphologically but also expresses various intestinal stem cell (ISC) markers. We hypothesized that ISC markers, Lgr5 (also a cancer stem cell marker), Ascl2 (fate determinator of ISC),Bmi1 (quiescent counterpart of Lgr5) and Cdx2 (primary regulator of ISC gene expression) have clinicopathological significance and could potentially be a predictor for survival in EAC. Methods Tissue microarray consisted of 64 EAC and 22 BE, and the expressions of Lgr5, Ascl2, Bmi1 and Cdx2 were analyzed using immunohistochemistry and scored independently by two pathologists. Clinicopathological factors (age, pathological grade and stage, affected lymph nodes, neoadjuvant therapy) were confounding factors, and univariable analysis using Fisher's exact tests as well as survival analysis using the Kaplan–Meier (KM) method and Cox proportional hazards regression (Cox PH) were performed to investigate its statistical significance. We performed a bioinformatic analysis of the TCGA dataset to validate the immunohistochemical findings. Results Among EAC, 69%, 88%, 64% and 70% expressed high Ascl2, Lgr5, Bmi1 and Cdx2, respectively. High Ascl2 and low Lgr5 expression significantly correlated to a higher number of involved lymph nodes; high Bmi1 expression significantly correlated to the pathological stage. Cdx2 was not correlated to any markers. KM analysis showed a negative impact of high Ascl2 expression on overall survival (OS; p = 0.0276) as well as progression-free survival (PFS; p = 0.0466), but not Lgr5, Bmi1 nor Cdx2. Cox PH analysis revealed Ascl2 (p = 0.011), and Cdx2 (p = 0.015) expression are independent prognostic factors for EAC. Conclusion Our results suggest that among the four ISC markers, Ascl2 and Cdx2 protein holds potential to be utilized as a prognostic biomarker. TCGA dataset revealed the association of ASCL2 mRNA expression with the number of positive lymph nodes but not overall survival, which implies further research is needed to explain the mechanism of Ascl2 overexpression in EAC carcinogenesis via ISC regulation.

Clinical and Lifestyle-Related Prognostic Indicators among Esophageal Adenocarcinoma Patients Receiving Treatment at a Comprehensive Cancer Center.

Simple SummaryEsophageal adenocarcinoma (EAC) is a highly lethal cancer with rising incidence in Western countries. Despite diagnostic and therapeutic advances, average 5-year EAC survival remains poor (~20%), with tumor stage and treatment the strongest prognostic factors. The role of lifestyle-related exposures remains uncertain. To address this gap, we analyzed survival associations among EAC patients treated at a tertiary cancer center. Importantly, this study is among the first to assess survival relationships by disease stage for several key lifestyle-related exposures (e.g., physical activity, medications, and diet), enabling us to identify associations which may have been obscured in past analyses. Our findings suggest that lifestyle interventions such as smoking cessation, exercise regimens, and use of cholesterol-lowering (statin) or anti-inflammatory (NSAID) medications may represent promising avenues to improve outcomes in this deadly cancer.Purpose: The incidence of esophageal adenocarcinoma (EAC) has risen substantially in recent decades, while the average 5-year survival remains only ~20%. Disease stage and treatment are the strongest prognostic factors. The role of lifestyle factors in relation to survival remains uncertain, with a handful of studies to date investigating associations with obesity, smoking, physical activity, diet, or medications. Methods: This study included patients diagnosed with primary adenocarcinoma of the esophagus, gastroesophageal junction, or cardia (N = 371) at Roswell Park Comprehensive Cancer Center between 2003 and 2019. Leveraging extensive data abstracted from electronic medical records, epidemiologic questionnaires, and a tumor registry, we analyzed clinical, behavioral, and environmental exposures and evaluated stage-specific associations with survival. Survival distributions were visualized using Kaplan–Meier curves. Cox proportional hazards regression models adjusted for age, sex, stage, treatment, and comorbidities were used to estimate the association between each exposure and all-cause or cancer-specific mortality. Results: Among patients presenting with localized/regional tumors (stages I–III), current smoking was associated with increased overall mortality risk (HR = 2.5 [1.42–4.53], p = 0.002), while current physical activity was linked to reduced risk (HR = 0.58 [0.35–0.96], p = 0.035). Among patients with stage IV disease, individuals reporting pre-diagnostic use of statins (HR = 0.62 [0.42–0.92], p = 0.018) or NSAIDs (HR = 0.61 [0.42–0.91], p = 0.016) had improved overall survival. Exploratory analyses suggested that high pre-diagnostic dietary consumption of broccoli, carrots, and fiber correlated with prolonged overall survival in patients with localized/regional disease. Conclusion: Our data suggest that lifestyle exposures may be differentially associated with EAC survival based on disease stage. Future investigation of larger, diverse patient cohorts is essential to validate these findings. Our results may help inform the development of lifestyle-based interventions to improve EAC prognosis and quality of life.

Prognostic Impact of the Presence of Barrett's Esophagus and Intestinal Metaplasia on Esophageal Adenocarcinoma Survival.

Barrett's esophagus (BE), defined by the presence of intestinal metaplasia (IM) on histology, is thought to be the only identifiable precursor lesion for esophageal adenocarcinoma (EAC). Recent studies have suggested the possibility of an alternate, non-IM associated EAC that is a more aggressive form of EAC with worse survival. Among EAC patients, we aimed to compare survival of patients with and without IM at the time of diagnosis. This was a retrospective cohort study of all patients with histologic confirmed EAC evaluated at a tertiary care center from 2013 to 2019. Cases were categorized according to the presence or absence of IM on histologic specimens (Group I-IM-EAC and Group II-non-IM-EAC). We compared demographic characteristics, clinical stage, therapy, and survival between the 2 groups using the Chi-square and ANOVA tests (for categorical and continuous variables, respectively). We used Cox proportional hazards regression to determine the association of IM with overall survival, adjusting for sex, age at diagnosis, tumor location, histologic grade, and clinical stage. A total of 475 patients were included in this analysis (mean age 64.8 years [SD 10.8], 89% white) and 109 (23.0%) had no evidence of IM. Compared with IM-EAC (Group I), individuals in the non-IM-EAC group were younger (P = .01) and had a greater proportion of patients diagnosed with advanced disease (49.5 vs 20.2% for stage 4, P < .001). These patients were less likely to undergo endoscopic therapy alone (0.92% vs 29.78%, P < .001) or surgery alone (0 vs 9.84%, P = .001). On multivariable analysis, the presence of IM-EAC was associated with improved overall survival compared to non-IM-EAC (HR 0.69, 95% CI 0.49-0.96). Additional factors associated with poor survival was increasing stage of diagnosis (HR 6.49: 95% CI 3.77-11.15 for stage 4, HR 2.19: 95% CI 1.25-3.84 for stage 3, HR 2.04: 95% CI 0.98-4.25 for stage 2 compared to stage 1) and more advanced histologic stage (HR 2.00, 95% CI 1.26-3.19) for poorly/undifferentiated compared to well differentiated). EAC without the presence of IM on histology was associated with worse survival compared to those with IM. Future prospective studies with detailed molecular sequencing are required to clarify if 2 separate phenotypes of EAC exist (IM-EAC and non-IM-EAC). If confirmed, this may have significant implications for screening and management strategies.

A DNA-damage immune response assay combined with PET biomarkers predicts response to neo-adjuvant chemotherapy and survival in oesophageal adenocarcinoma

18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26–0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26–0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.