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Esophageal inlet patch (EIP) adenocarcinoma is extremely rare. We present a case of a 58-year-old man who underwent a diagnostic esophagogastroduodenoscopy for dysphagia and found to have a 2 cm polypoid mass arising from an EIP. Biopsies and staging were consistent with T1aN0M0 EIP adenocarcinoma. While surgical resection was the main method of treatment of these lesions, very few case reports have shown that endoscopic resection can successfully remove these lesions. After multidisciplinary discussion, the patient underwent curative traction-assisted endoscopic submucosal dissection-which is the first known case report to highlight the success of this technique.

Background: Prognosis of esophageal adenocarcinoma (EAC) is still poor. Therefore, the development of novel therapeutic modalities is necessary to improve therapeutic outcomes in EAC. Here, we report a novel promoter-controlled oncolytic adenovirus targeting CDX2 (Ad5/3-pCDX2) and its specific anticancer effect for EAC. Methods: We used OE19, OE33, HT29, MKN28, RH30, and HEL299 cell lines. To establish CDX2 overexpressing OE19 cells, pCMV-GLI1 plasmid was transfected to OE19 (OE19 + GLI1). The virus replication and cytocidal effect of replication competent Ad5/3-pCDX2 were analyzed in vitro. Antitumor effect of Ad5/3-pCDX2 was assessed in xenograft mouse models by intratumoral injection of the viruses. Finally, efficacy of combination therapy with Ad5/3-pCDX2 and 5FU was evaluated. Results: EAC cells and HT29 showed high mRNA levels of CDX2, but not MKN28, RH30, and HEL299. We confirmed that deoxycholic acid (DCA) exposure enhanced CDX2 expression in EAC cells and OE19 + GLI1 had persistent CDX2 overexpression without DCA. Ad5/3-pCDX2 showed stronger cytocidal effect in OE19 + GLI1 than OE19, whereas Ad5/3-pCDX2 did not kill CDX2-negative cells. Ad5/3-pCDX2 was significantly replicated in EAC cells and the virus replication was higher in OE19 + GLI1 and OE19 with DCA compared to OE19 without DCA exposure. In vivo, Ad5/3-pCDX2 significantly suppressed OE19 tumor growth and the antitumor effect was enhanced in OE19 + GLI1 tumor. In contrast, Ad5/3-pCDX2 did not show significant antitumor effect in MKN28 tumor. Moreover, Ad5/3-pCDX2 significantly increased the efficacy of 5FU in vitro and in vivo. Conclusions: Ad5/3-pCDX2 showed specific anticancer effect for EAC, which was enhanced by bile acid exposure. Ad5/3-pCDX2 has promising potential for EAC therapy in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Screening for Barrett's esophagus (BE) remains controversial, even for high-risk populations. Our study aimed to evaluate the proportion of patients diagnosed with esophageal adenocarcinoma (EAC) who were not screened for BE or did not receive recommended BE surveillance screening. We then evaluated the relationship between cancer staging and screening/surveillance opportunities. Methods: This single-center retrospective study included 187 patients from January 2016 to January 2022 with newly diagnosed EAC. Data extracted from patient charts included BE risk factors, and BE, endoscopic, and histologic history. Results: A total of 187 patients had a new diagnosis of EAC. Among this group, 44% had appropriate BE surveillance adherence, and 47% of patients met the criteria for BE screening but had not been screened prior to EAC diagnosis. Adherence to BE surveillance was associated with earlier stages of cancer on biopsy. No significant difference in cancer staging was found in those with missed BE screening opportunities. Discussion: Patients with a diagnosis of BE who adhered to surveillance guidelines had earlier stage EAC at diagnosis, which emphasizes the importance of surveillance. Most of those with an initial diagnosis of EAC had not received any BE screening. [ABSTRACT FROM AUTHOR]

ABSTRACT Esophageal adenocarcinoma and diet are not well understood to be associated. We conducted Mendelian randomization analysis using 18 dietary factors as exposures (primarily including fruit consumption, vegetable consumption, alcohol consumption, meat consumption, tea intake, fish intake, etc.), with esophageal adenocarcinoma as the outcome. The IVW method was the leading method used for detecting causal links. Cochran's Q test was utilized to assess heterogeneity, the intercept of the MR‐Egger method was used to assess the presence of horizontal pleiotropy, and the existence of outliers was identified via the MR‐Presso method. This study identified that both alcohol intake frequency (OR = 1.375, p = 0.0216) and coffee intake (OR = 2.680, p = 0.0304) were linked to a heightened risk of esophageal adenocarcinoma, while raw vegetable/salad consumption (OR = 0.117, p = 0.0258) and dried fruit intake (OR = 0.229, p = 0.00235) were associated with a decreased risk of esophageal adenocarcinoma. After FDR correction, only dried fruit intake (q = 0.0423) remained statistically significant. However, there was no evidence linking the other 14 dietary variables to esophageal adenocarcinoma. This study observed that alcohol consumption and coffee intake increase the risk of esophageal adenocarcinoma, while the intake of dried fruits rather than fresh fruits and raw vegetable intake rather than cooked vegetable intake reduce the risk of esophageal adenocarcinoma. Other dietary factors were not associated with the risk of esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer management lacks reliable response predictors to chemotherapy. In this study we evaluated the feasibility and accuracy of Biodynamic Imaging (BDI), a technology that employs digital holography as a rapid predictor of chemotherapy sensitivity in locoregional esophageal adenocarcinoma. Methods: Pre-treatment endoscopic pinch biopsies were collected from patients with esophageal adenocarcinoma during standard staging procedures. BDI analyzed the tumor samples and assessed in vitro chemotherapy sensitivity. BDI sensitivity predictions were compared to patients' pathological responses, the gold standard for determining clinical response, in the surgically treated subset (n=18). Result: BDI was feasible with timely tissue acquisition, collection, and processing in all 30 enrolled patients and successful BDI analysis in 28/29 (96%) eligible. BDI accurately predicted chemotherapy response in 13/18 (72.2%) patients using a classifier for complete, marked, and partial/no-response. BDI technology had 100% negative predictive value for complete pathological response hence identifying patients unlikely to respond to treatment. Conclusion: BDI technology can potentially predict patients' response to platinum chemotherapy. Additionally, this technology represents a promising step towards optimizing treatment strategies for esophageal adenocarcinoma patients by pre-emptively identifying non-responders to conventional platinumbased chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Obesity is a risk factor for esophageal adenocarcinoma (EAC). It was reported that obesity -associated inflammation correlates with insulin resistance and increased risk of EAC. The objective of the study is to investigate the role of obesity associated inflammatory mediators in the development of EAC. Methods: We included 23 obese and nonobese patients with EAC or with or without Barrett's esophagus (BE) after IRB approval. We collected 23 normal, 10 BE, and 19 EAC tissue samples from endoscopy or esophagectomy. The samples were analyzed for the expression levels of pro-apoptotic and anti-apoptotic factors, PKC-δ, cIAP2, FLIP, IGF-1, Akt, NF-kB and Ki67 by immunofluorescence and RT-PCR. We compared the expression levels between normal, BE, and EAC tissue using Students' t-test between two groups. Results: Our results showed decreased gene and protein expression of pro-apoptotic factors (bad, bak and bax) and increased expression of anti-apoptotic factors (bcl-2, Bcl-xL) in BE and EAC compared to normal tissues. There was increased gene and protein expression of PKC-δ, cIAP2, FLIP, NF-kB, IGF-1, Akt, and Ki67 in BE and EAC samples compared to normal esophagus. Further, an increased folds changes in mRNA expression of proapoptotic factors, antiapoptotic factors, PKC-δ, IGF-1, Akt, and Ki-67 was associated with obesity. Conclusion: Patients with EAC had increased expression of cIAP2 and FLIP, and PKC-δ which is associated with inhibition of apoptosis and possible progression of esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

The relationship between 'bulky' locoregional lymphadenopathy and survival has not been investigated in the setting of esophageal adenocarcinoma (EAC). This study aimed to explore whether bulky regional lymphadenopathy at diagnosis affected survival outcomes in patients with EAC treated with neoadjuvant chemotherapy and en bloc resection. A single-center retrospective review of a prospectively maintained upper GI cancer surgical database was performed between January 2012 and December 2019. Patients with locally advanced EAC (cT2-3, N+, M0) treated with neoadjuvant docetaxel-based chemotherapy and transthoracic en bloc esophagogastrectomy were identified. Computed tomography scans from before the initiation of treatment were reviewed, and patients were stratified according to whether bulky loco-regional lymph nodes were present. This was defined as lymphadenopathy >2 cm in any axis. Overall survival was compared, and a Cox multivariate regression model was calculated. Two hundred twenty-five of the eight hundred seventy patients identified met the inclusion criteria. Forty-eight (21%) had bulky lymphadenopathy, leaving 177 allocated to the control group. More patients with bulky lymphadenopathy had ypN3 disease (18/48, 38% vs. 39/177, 20%, P  = 0.025). Among patients with bulky lymphadenopathy, overall survival was generally worse (32.6 vs. 59.1 months, P  = 0.012). However, among the 9/48 (19%) patients with bulky lymphadenopathy who achieved ypN− status survival outcomes were similar to those with non-bulky lymphadenopathy who also achieved lymph node sterilization. Poor differentiation (HR 1.8, 95% CI 1.0–2.9, P  = 0.034), ypN+ (HR 1.9, 95% CI 1.1–3.6, P  = 0.032), and bulky lymphadenopathy were independently associated with an increased risk of death (HR 1.7, 1.0–2.9, P  = 0.048). Bulky regional lymphadenopathy is associated with a poor prognosis. Efforts to identify the ideal treatment regimen for these patients are urgently required. [ABSTRACT FROM AUTHOR]

Background: Adenocarcinoma of the esophagogastric junction (AEGJ) is most common in men and the elderly, but the disease is becoming more common in female and young adult persons. We have investigated the clinicoepidemiological characteristics of female and young adult patients with AEGJ and the 12-year trends in the Kurashiki area for young adult patients with AEGJ. Methods: Patients diagnosed with AEGJ in 12 hospitals between January 2008 and December 2019 were included in this study. Patients were divided into three groups by age (young adult [≤50 years], middle-aged [51 to 70 years], and elderly [>70 years]). Factors associated with AEGJ such as obesity, smoking, hiatal hernia and male, which were reported in our previous study, were identified. Results: One hundred and eighty-eight AEGJ patients, including 36 females and 20 young adults, were characterized. There was no significant change in the annual incidence of AEGJ among female (p=0.078) and young adult patients (p=0.89). Female patients without any associated factors, accounting for 53% (19/36) of the female patients and young adult patients, had significantly more histologically undifferentiated cancers than patients with at least one associated factor (58% [11/19] vs. 30% [50/169], p=0.025) and middle-aged and elderly patients (60% [12/20] vs. 30% [25/83] vs. 28% [24/85], p =0.026). Smoking was significantly less common in women than in men (8% [3/36] vs. 57% [87/152], p < 0.01). There were no significant differences between ages in the proportions of these associated factors. Conclusions: Histologically undifferentiated AEGJ cancers were more frequent in female patients without any associated factors and in young adult patients. Factors associated with AEGJ may differ between women and men, but they are similar in young adults and older adults. No increase in young adult patients with AEGJ was observed in the 12-year study. [ABSTRACT FROM AUTHOR]

Background: The cancer risk for each length of Barrett's esophagus (BE) in Japanese is unknown. This nationwide, multi-institutional study aims to clarify the cancer risk by length of BE in the general Japanese population. Methods: Consecutive subjects who underwent upper endoscopic screening at 17 centers between 2013 and 2017 and had at least one follow-up endoscopy by December 2022 were included. The presence/absence of BE and, if present, its length were retrospectively assessed using the retrieved endoscopic images recorded at baseline. Information on the subsequent occurrence of esophageal adenocarcinoma and other upper gastrointestinal cancers was also collected. Cancer incidence was calculated and expressed as %/year. Results: A total of 33,478 subjects were enrolled, and 17,884 (53.4%), 10,641 (31.8%), 4889 (14.6%), and 64 (0.2%) were diagnosed as absent BE, BE < 1 cm, 1–3 cm, and ≥ 3 cm, respectively. During a median follow-up of 80 months, 11 cases of esophageal adenocarcinoma developed. The annual incidence of esophageal adenocarcinoma is 0%/year for absent BE, 0.0032 (0.00066–0.013)%/year for BE < 1 cm, 0.026 (0.011–0.054)%/year for 1–3 cm, and 0.58 (0.042–2.11)%/year for ≥ 3 cm, respectively. Meanwhile, the incidence of esophageal squamous cell carcinoma and gastric cancer were 0.039 (0.031–0.049)%/year and 0.16 (0.14–0.18)%/year, respectively. Conclusions: By enrolling a large number of subjects with long-term follow-up, this study demonstrated that the risk of cancer increased steadily with increasing length of BE in the Japanese population. Therefore, it is important to consider the length of BE when determining the management strategy for BE. [ABSTRACT FROM AUTHOR]

Background: The significance of lymphovascular invasion (LVI) in esophageal adenocarcinoma (EAC) has not yet been described. Potential utility as an adjunct to current staging guidelines remains unknown. Methods: The National Cancer Database was queried from 2006 to 2020. Univariate and multivariable models, Kaplan Meier method, and log-rank test were used. Subgroup analyses by pN stage were conducted. Results: Of 9,689 patients, 23.2% had LVI. LVI was an independent prognostic factor (hazard ratio [HR] 1.401, 95% confidence interval [CI] 1.307–1.502, p < 0.0001) with reduction in median survival to 20.0 months (95% CI 18.9–21.4) from 39.7 months (95% CI 37.8–42.3, p < 0.0001). Multivariable survival analysis adjusted on pN and pT stage found that patients with LVI had decreased survival in a given pN stage (p < 0.001). pN0/LVI+ patients had a similar prognosis to the higher staged pN1/LVI− (28.6 months), although pN1/LVI− patients did slightly worse (p = 0.0135). Additionally, patients with pN1/LVI+ had equivalent survival compared with pN2/LVI− (p = 0.178) as did pN2/LVI+ patients compared with pN3/LVI− (p = 0.995). Conclusions: In these data, LVI is an independent negative prognostic factor in EAC. LVI was associated with a survival reduction similar to an upstaged nodal status irrespective of T stage. Patients with LVI may be better classified at a higher pN stage. [ABSTRACT FROM AUTHOR]

Simple Summary: Esophageal adenocarcinoma (EAC) is one of the deadliest malignancies in the United States (US) and the only major cancer in the US with an increasing incidence. Although recent advances have been made in surgery, radiation, and systemic medications, outcomes remain poor. Therefore, new beneficial treatment approaches are crucially desired. Obesity is associated with EAC and abnormalities in insulin-like growth factor-1 (IGF-1) and insulin signaling. However, the effect of blocking IGF-1 receptor/insulin receptor (IGF-1 R/IR) signaling is not well studied in EAC. Here, BMS-754807, a robust small-molecule inhibitor of IGF-1R/IR signaling, inhibited not only EAC cell growth but also EAC cell migration both as a monotherapy and in combination with the chemotherapy nanoparticle albumin-bound paclitaxel (nab-paclitaxel). In addition, BMS-754807 along with nab-paclitaxel significantly reduced EAC mice tumor growth, with enhanced mice survival. Interestingly, the combination of BMS-754807 and nab-paclitaxel showed an additive effect on tumor growth inhibition and survival benefit, indicating this combination as a novel option for EAC therapy. The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor budding (TB), poorly differentiated clusters (PDCs), and the Stroma AReactive Invasion Front Area (SARIFA) are emerging biomarkers offering fast and cost-effective ways of assisting the clinical therapeutic decision. However, in esophageal cancers, their applicability has not been fully elucidated. In our retrospective study, we examined these invasion markers in a cohort of esophageal squamous cell cancers and adenocarcinomas, with a special focus on lymphatic spread. According to our results, different invasive patterns are prognostic in histological subtypes of esophageal cancer, namely, SARIFA in adenocarcinomas and TB in squamous cell carcinomas. However, only in squamous cell cancers were TB and PDC useful for the prediction of overall survival. In adenocarcinomas, neither of the aforementioned markers were significant regarding survival prediction, possibly due to the small cohort size. Both esophageal squamous cell carcinoma (ESQCC) and adenocarcinoma (EAC) are known to have poor prognosis. We aimed to investigate the invasion front areas of 57 ESQCC and 43 EAC cases to find histological signs of metastatic progression. Tumor cell clusters with different cell counts, including tumor buds (TBs) and poorly differentiated clusters (PDCs), were assessed. The presence of the recently described Stroma AReactive Invasion Front Area (SARIFA) phenomenon, which defines a direct contact between tumor cells and adipocytes, was more frequently observed in EAC than in ESQCC (p = 0.004). In adenocarcinomas, a higher prevalence of SARIFA was observed in tumors with a higher number of small clusters (TBs and small PDCs; p < 0.001); furthermore, both the high number of TBs (p = 0.016) and the presence of SARIFA (p = 0.001) correlated with a higher pT stage. SARIFA positivity in EAC (p = 0.011) and high TB in ESQCC (p = 0.0006) were found to be independent prognostic factors for lymph node metastases. Moreover, in ESQCC, the higher absolute number of both TBs and PDCs was associated with shorter overall survival (p = 0.0269 and p = 0.0377, respectively). Our results suggest that the histological subtypes of esophageal cancer behave differently, namely, that different features of the invasion front are of prognostic significance. [ABSTRACT FROM AUTHOR]

In esophageal adenocarcinoma, the presence of lymph node metastases predicts patients' survival even after curative resection. Currently, there is no highly accurate marker for detecting the presence of lymph node metastasis. The SEMA3F/NRP2 axis was initially characterized in axon guidance and recent evidence has revealed its significant involvement in lymphangiogenesis, angiogenesis, and carcinogenesis. Hence, the objective of this study was to elucidate the roles of SEMA3F and its receptor NRP2 in esophageal adenocarcinoma. We conducted an immunohistochemical evaluation of SEMA3F and NRP2 protein expression in 776 patients with esophageal adenocarcinoma who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. Total and positive cancer cell counts were digitally analyzed using QuPath and verified by experienced pathologists to ensure accuracy. Positive expression was determined as a cell percentage exceeding the 50th percentile threshold. In our cohort, patients exhibiting SEMA3F positive expression experience significantly lower pT- and pN-stages. In contrast, positive NRP2 expression is associated with the presence of lymph node metastases. Survival analyses showed that the expression status of NRP2 had no impact on patient survival. However, SEMA3F positivity was associated with a favorable patient survival outcome (median OS: 38.9 vs. 26.5 months). Furthermore, SEMA3F could be confirmed as an independent factor for better patient survival in patients with early tumor stage (pT1N0-3: HR = 0.505, p = 0.014, pT1-4N0: HR = 0.664, p = 0.024, pT1N0: HR = 0.483, p = 0.040). In summary, SEMA3F emerges as an independent predictor for a favorable prognosis in patients with early-stage esophageal adenocarcinoma. Additionally, NRP2 expression is linked to a higher risk of lymph node metastases occurrence. We hypothesize that low SEMA3F expression could identify patients with early-stage tumors who might benefit from more aggressive treatment options or intensified follow-up. Furthermore, SEMA3F and its associated pathways should be explored as potential tumor-suppressing agents. [ABSTRACT FROM AUTHOR]

Barrett's esophagus (BE) is a common precancerous lesion that can progress to esophageal adenocarcinoma (EAC). There are significant alterations in the esophageal microbiome in the progression from healthy esophagus to BE to EAC, including an increased abundance of a variety of lactate-producing bacteria and an increase of lactate in the tumor microenvironment, as predicted by metabolic modeling. The role of bacterial lactate in EAC is unknown. Here, we utilize patient-derived organoid (PDO) models of EAC and demonstrate that lactate inhibits the growth and proliferation of EAC PDOs through alterations in the tumor NADH/NAD+ redox state. Further RNA sequencing of EAC PDOs identifies ID1 and RSAD2 as potential regulatory molecules crucial in mediating lactate's ability to suppress glycolysis and proliferation. Gene ontology analysis also identifies the activation of inflammatory and immunological pathways in addition to alterations in the metabolic pathways in EAC PDOs exposed to lactate, suggesting a multi-faceted role for lactate in the pathogenesis of EAC. [ABSTRACT FROM AUTHOR]

Esophageal adenocarcinoma (EAC) is a subtype of esophageal cancer that is difficult to treat, with overall poor survival and frequent recurrence despite curative-intent treatment strategies. There is limited understanding of EAC resistance mechanisms to chemotherapy or radiation. We have found that the AMP-activated protein kinase (AMPK) can serve a pro-survival function in EAC cells in response to cytotoxic treatments. Treatment with the IL-6 inhibitor tocilizumab, which previously has been shown to inhibit EAC organoid growth, resulted in the activation of AMPK in the OE33 EAC cell line, which was accompanied by a decrease in MTORC1 signaling and an increase in oxidative mitochondrial metabolism, both known downstream effects of AMPK activation to promote cell survival under conditions of metabolic stress. This increase in oxidative metabolism was abrogated in cells with a genetic knockdown of AMPK expression. Furthermore, we found that AMPK was activated in OE33 cells following treatment with cisplatin or ionizing radiation. Treatment with the AMPK inhibitor Compound C or genetic knockdown of AMPK expression enhanced cell death in a synergistic manner with chemotherapeutics or ionizing radiation. These findings were recapitulated in human patient-derived EAC organoids, suggesting that AMPK may be a common pro-survival mechanism to confer treatment resistance in EAC and may serve as a novel target to enhance the efficacy of current and future treatment strategies. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Screening for early esophageal adenocarcinoma (EAC) may potentially reduce EAC-related mortality and morbidity. This study aimed to examine the Dutch population's intended uptake of 3 hypothetical EAC screening test scenarios and preferences for potential future organization. METHODS: A total of 8,350 Dutch individuals aged 45-75 years were invited, of whom 2,258 completed a web-based survey. Participants were randomly assigned to 1 of 3 hypothetical screening test scenarios (i.e., transnasal endoscopy, ingestible cell collection device, or breath analysis). The primary outcome was intended uptake. Secondary outcomes included acceptance of screening eligibility criteria and preferences regarding invitation, counseling, and diagnostic follow-up. We performed exploratory univariable and multivariable regression analyses to assess which determinants were associated with EAC screening intent. RESULTS: Intended uptake of screening was highest in the breath analysis scenario (95%), followed by conventional upper endoscopy (78%), an ingestible cell collection device (75%), and transnasal endoscopy (68%) (P < 0.001). Anticipating discomfort was most strongly associated with decreased intention to undergo transnasal endoscopy (odds ratio 0.18, 95% confidence interval 0.11-0.29) or swallow a cell collection device (odds ratio 0.20, 95% confidence interval 0.13-0.32). Cancer worry and high acceptance of test sensitivity/specificity were consistently associated with a positive intention to participate in screening. Inviting persons for screening based on gastroesophageal reflux disease symptoms, age, or the output of a risk prediction model was acceptable to 74%, 69%, and 66%, respectively. Inviting only men was acceptable for only 41% of women. The majority (58%) preferred to be invited by a public health organization, and 32% of the participants preferred to discuss their decision to participate with a healthcare professional. DISCUSSION: Participants in this study self-selected through a web-based survey, potentially introducing selection bias. Participants generally intended to participate in EAC screening, although the level of intent depended on the discomfort and performance associated with the offered screening test. Determining eligibility based on gastroesophageal reflux disease symptoms, age, or a risk calculator, but not sex, would be acceptable to most individuals. [ABSTRACT FROM AUTHOR]

Induction of apoptosis in tumor cells is one of the best ways to cure cancer. While most apoptosis requires a chain of caspase activation, CASP2 can do this all by itself. The matricellular protein cellular communication network 1 (CCN1) is known for supporting some cancer growth but suppressing others. Esophageal adenocarcinoma (EAC) belongs to the latter. CCN1 is capable of inducing TRAIL‐mediated apoptosis in EAC cells. This study found that CCN1 upregulated CASP2 transcription but not its translation in EAC cells because, on one hand, CCN1 downregulated p16 and p21, which increased RB1 phosphorylation allowing E2F1 to transcribe more CASP2 mRNA, on the other hand, CCN1 also upregulated HuR, which is bound to CASP2 mRNA species and blocked its protein translation. As a result, CASP2 contributed nothing to CCN1‐induced EAC cell apoptosis. On the contrary, CCN1 promoted CASP3, not only in its transcription but also in its translation and activation, which established the basis for CCN1‐induced EAC cell apoptosis. [ABSTRACT FROM AUTHOR]

Background and Aim: Various deep learning models, based on convolutional neural network (CNN), have been shown to improve the detection of early esophageal neoplasia in Barrett's esophagus. Vision transformer (ViT), derived from natural language processing, has emerged as the new state‐of‐the‐art for image recognition, outperforming predecessors such as CNN. This pilot study explores the use of ViT to classify the presence or absence of early esophageal neoplasia in endoscopic images of Barrett's esophagus. Methods: A BO dataset of 1918 images of Barrett's esophagus from 267 unique patients was used. The images were classified as dysplastic (D‐BO) or non‐dysplastic (ND‐BO). A pretrained vision transformer model, ViTBase16, was used to develop our classifier models. Three ViT models were developed for comparison based on imaging modality: white‐light imaging (WLI), narrow‐band imaging (NBI), and combined modalities. Performance of each model was evaluated based on accuracy, sensitivity, specificity, confusion matrices, and receiver operating characteristic curves. Results: The ViT models demonstrated the following performance: WLI‐ViT (Accuracy: 92%, Sensitivity: 82%, Specificity: 95%), NBI‐ViT (Accuracy: 99%, Sensitivity: 97%, Specificity: 99%), and combined modalities‐ViT (Accuracy: 93%, Sensitivity: 87%, Specificity: 95%). Combined modalities‐ViT showed greater accuracy (94% vs 90%) and sensitivity (80% vs 70%) compared with WLI‐ViT when classifying WLI images on a subgroup testing set. Conclusion: ViT exhibited high accuracy in classifying the presence or absence of EON in endoscopic images of Barrett's esophagus. ViT has the potential to be widely applicable to other endoscopic diagnoses of gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Adenocarcinoma of the esophagogastric junction (AEGJ) is most common in men and the elderly, but the disease is becoming more common in female and young adult persons. We have investigated the clinicoepidemiological characteristics of female and young adult patients with AEGJ and the 12-year trends in the Kurashiki area for young adult patients with AEGJ. Methods Patients diagnosed with AEGJ in 12 hospitals between January 2008 and December 2019 were included in this study. Patients were divided into three groups by age (young adult [≤50 years], middle-aged [51 to 70 years], and elderly [>70 years]). Factors associated with AEGJ such as obesity, smoking, hiatal hernia and male, which were reported in our previous study, were identified. Results One hundred and eighty-eight AEGJ patients, including 36 females and 20 young adults, were characterized. There was no significant change in the annual incidence of AEGJ among female (p=0.078) and young adult patients (p=0.89). Female patients without any associated factors, accounting for 53% (19/36) of the female patients and young adult patients, had significantly more histologically undifferentiated cancers than patients with at least one associated factor (58% [11/19] vs. 30% [50/169], p=0.025) and middle-aged and elderly patients (60% [12/20] vs. 30% [25/83] vs. 28% [24/85], p =0.026). Smoking was significantly less common in women than in men (8% [3/36] vs. 57% [87/152], p < 0.01). There were no significant differences between ages in the proportions of these associated factors. Conclusions Histologically undifferentiated AEGJ cancers were more frequent in female patients without any associated factors and in young adult patients. Factors associated with AEGJ may differ between women and men, but they are similar in young adults and older adults. No increase in young adult patients with AEGJ was observed in the 12-year study.

Abstract In esophageal adenocarcinoma, the presence of lymph node metastases predicts patients' survival even after curative resection. Currently, there is no highly accurate marker for detecting the presence of lymph node metastasis. The SEMA3F/NRP2 axis was initially characterized in axon guidance and recent evidence has revealed its significant involvement in lymphangiogenesis, angiogenesis, and carcinogenesis. Hence, the objective of this study was to elucidate the roles of SEMA3F and its receptor NRP2 in esophageal adenocarcinoma. We conducted an immunohistochemical evaluation of SEMA3F and NRP2 protein expression in 776 patients with esophageal adenocarcinoma who underwent Ivor-Lewis esophagectomy at the University Hospital of Cologne. Total and positive cancer cell counts were digitally analyzed using QuPath and verified by experienced pathologists to ensure accuracy. Positive expression was determined as a cell percentage exceeding the 50th percentile threshold. In our cohort, patients exhibiting SEMA3F positive expression experience significantly lower pT- and pN-stages. In contrast, positive NRP2 expression is associated with the presence of lymph node metastases. Survival analyses showed that the expression status of NRP2 had no impact on patient survival. However, SEMA3F positivity was associated with a favorable patient survival outcome (median OS: 38.9 vs. 26.5 months). Furthermore, SEMA3F could be confirmed as an independent factor for better patient survival in patients with early tumor stage (pT1N0-3: HR = 0.505, p = 0.014, pT1-4N0: HR = 0.664, p = 0.024, pT1N0: HR = 0.483, p = 0.040). In summary, SEMA3F emerges as an independent predictor for a favorable prognosis in patients with early-stage esophageal adenocarcinoma. Additionally, NRP2 expression is linked to a higher risk of lymph node metastases occurrence. We hypothesize that low SEMA3F expression could identify patients with early-stage tumors who might benefit from more aggressive treatment options or intensified follow-up. Furthermore, SEMA3F and its associated pathways should be explored as potential tumor-suppressing agents.

BACKGROUND: Novel, less-invasive technologies to screen for Barretts esophagus (BE) may enable a paradigm shift in early detection strategies for esophageal adenocarcinoma (EAC). Understanding professionals perspectives on screening is important to determine how to proceed. We aimed to explore and compare professionals perceptions of screening for BE and EAC screening in three countries. METHODS: In this study, 29 Dutch, 20 British and 18 American health care professionals (clinicians, researchers and policy makers) participated in concept mapping: a mixed-methods consensus building methodology. Statements on perceived barriers, facilitators, advantages, disadvantages, implications or worries associated with screening for BE and EAC were collected in asynchronous digital brainstorm sessions. Subsequently, participants sorted the statements into groups according to thematic similarity and assessed the relevance of each statement in evaluating the acceptability of BE and EAC screening. Multidimensional scaling and cluster analysis were used to map the associations between generated statements. RESULTS: Professionals across three countries identified eight consistent themes that relate to their perceptions of screening for BE and EAC: (1) Benefits, (2) Harms, (3) Clinical effectiveness concerns, (4) Screening population, (5) Screening modality, (6) Resources, (7) Ownership, and (8) Public communication. Dutch and American professionals prioritized the potential health benefits of screening but also questioned clinical impact. In contrast, British participants prioritized identification of the screening population and suitable test. CONCLUSIONS: Most professionals see potential in less-invasive screening tests for BE and EAC but underline the need to define the target screening population and determine benefits and harms before widely employing them. Successful implementation will require thoughtful consideration of the involvement of general practitioners, readiness of endoscopy and pathology services, balanced public communication, and country-specific regulations.

Accessory gallbladders are rare congenital malformations of the hepatobiliary system. They are often incidentally diagnosed preoperatively or intra-operatively. We report a case of a 52-year-old man with an accessory gallbladder that was partially encased by esophageal adenocarcinoma. To the best of our knowledge, this is the first reported case of an accessory gallbladder diagnosed concurrently with esophageal adenocarcinoma. It is important for clinicians and radiologists to be cognizant of this anatomical malformation to avoid misdiagnoses and intra-operative complications.

Accelerated biological aging may be associated with increased risk of esophageal adenocarcinoma (EAC). However, its relationship with genetic variation, and its effect on improving risk population stratification, remains unknown. We performed an exposome association study to determine potential associated factors associated with EAC. To quantify biological age and its difference from chronological age, we calculated the BioAge10 and Biological Age Acceleration (BioAgeAccel) based on chronological age and nine biomarkers. Multivariable Cox regression models for 362,310 participants from the UK Biobank with a median follow‐up of 13.70 years were performed. We established a weighted polygenic risk score (wPRS) associated with EAC, to assess joint and interaction effects with BioAgeAccel. Four indicators were used to evaluate their interaction effects, and we fitted curves to evaluate the risk stratification ability of BioAgeAccel. Compared with biologically younger participants, those older had higher risk of EAC, with adjusted HR of 1.79 (95%CI: 1.52–2.10). Compared with low wPRS and biologically younger group, the high wPRS and biologically older group had a 4.30‐fold increase in HR (95% CI: 2.78–6.66), at meanwhile, 1.15‐fold relative excess risk was detected (95% CI: 0.30–2.75), and 22% of the overall EAC risk was attributable to the interactive effects (95% CI: 12%–31%). The 10‐year absolute incidence risk indicates that biologically older individuals should begin screening procedures 4.18 years in advance, while youngers can postpone screening by 4.96 years, compared with general population. BioAgeAccel interacted positively with genetic variation and increased risk of EAC, it could serve as a novel indicator for predicting incidence. [ABSTRACT FROM AUTHOR]

Purpose of Review: Obesity and related comorbidities are on the rise, with trends showing that nearly half of the United States population will be obese by 2030. This review focuses on the pathophysiology of esophageal disorders in patients with obesity as well as treatment considerations for obesity in patients with esophageal disorders. Recent Findings: Gastroesophageal reflux disease (GERD) is prevalent in approximately 20% of patients with obesity and is associated with multiple underlying anatomic risk factors. In addition, systemic and paracrine proinflammatory effects mediated by visceral adipose tissue also contribute to the development of GERD-related complications such as erosive esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Esophageal dysmotility is also common in obesity, although with varying clinical impact as the majority of patients are asymptomatic. Although data regarding laparoscopic sleeve gastrectomy and GERD is conflicting, Roux-en-Y gastric bypass is considered the preferred surgical approach for obesity in patients with GERD. Recent data signal that newer anti-obesity medications like glucagon-like peptide 1 (GLP-1) agonists may lead to increased GERD and related complications; however, data on this subject is limited. Summary: Esophageal dysfunction is prevalent in patients with obesity and should be carefully evaluated prior to considering treatment for obesity such as bariatric surgery or antiobesity medications. [ABSTRACT FROM AUTHOR]

Aim: to present data on the role of bile acids in the progression of Barrett's esophagus (BE) and the development of esophageal dysplasia and adenocarcinoma and to provide a rationale for the use of ursodeoxycholic acid in addition to basic therapy in patients with gastroesophageal reflux disease (GERD).Key points. The prevalence of GERD in the world is 13.98 %. In the absence of the necessary treatment or non-compliance with the recommended regimens and duration of drug use, complications of GERD develop such as stricture, bleeding, BE, which, in turn, is a risk factor for the development of esophageal adenocarcinoma (EAC). The basic therapy for GERD is proton pump inhibitors (PPIs), but up to 40 % of patients do not fully respond to PPI monotherapy, which indicates the need to consider, among the factors in the pathogenesis of GERD, the persistence of weakly acidic and weakly alkaline refluxes, the presence of which can be diagnosed by performing 24-hour impedance-pH monitoring. It has been proven that refluxate is predominantly acidic in nature in 50 % of patients with GERD, acidic with a bile component in 39.7 %, and 10.3 % of patients have bile reflux. The weaklly alkaline nature of reflux, due to the presence of duodenal contents, significantly increases the incidence of intestinal metaplasia with dysplasia and EAC compared to acidic pH values. Therefore, stopping duodenal reflux may be an important step in preventing the development of EAC. Among the components of duodenal contents that have a damaging effect on the mucous membrane of the esophagus, the role of bile acids has been most studied. The presence of hydrophobic bile acids, namely deoxycholic acid (DCA), is associated with oxidative DNA damage in lesions of intestinal-type columnar cell metaplasia. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, is a natural competitive inhibitor of DCA and prevents DNA damage and nuclear factor-κB (NF-κB) activation caused by toxic bile acids in BE epithelial cells. The cytoprotective effect of UDCA, aimed at preventing DNA damage and increasing the reparative capacity of cells in the metaplastic epithelium of the BE, allows us to consider this drug as a means of chemoprophylaxis in patients diagnosed with GERD.Conclusion. The addition of UDCA drugs to the basic therapy is pathogenetically justified in patients with GERD in the presence of duodenogastroesophageal reflux. Prescribing complex therapy will reduce the incidence of esophagitis, progression of BE with the development of dysplasia and adenocarcinoma caused by exposure to bile acids.

Abstract The incidence of esophageal adenocarcinoma (EAC) has surged by 600% in recent decades, with a dismal 5-year survival rate of just 15%. Barrett’s esophagus (BE), affecting about 2% of the population, raises the risk of EAC by 40-fold. Despite this, the transcriptomic changes during the BE to EAC progression remain unclear. Our study addresses this gap through comprehensive transcriptomic profiling to identify key mRNA signatures and genomic alterations, such as gene fusions. We performed RNA-sequencing on BE and EAC tissues from 8 individuals, followed by differential gene expression, pathway and network analysis, and gene fusion prediction. We identified mRNA changes during the BE-to-EAC transition and validated our results with single-cell RNA-seq datasets. We observed upregulation of keratin family members in EAC and confirmed increased levels of keratin 14 (KRT14) using immunofluorescence. More differentiated BE marker genes are downregulated during progression to EAC, suggesting undifferentiated BE subpopulations contribute to EAC. We also identified several gene fusions absent in paired BE and normal esophagus but present in EAC. Our findings are critical for the BE-to-EAC transition and have the potential to promote early diagnosis, prevention, and improved treatment strategies for EAC.

Tumor-to-tumor metastasis is a known but rare occurrence and is characterized as 2 distinct tumor types in same anatomic location. We present a rare case of intracranial tumor-to-tumor metastasis of esophageal adenocarcinoma into meningioma. Our case emphasizes the rare occurrence of intracranial tumor-to-tumor metastasis and importance of histology and immunohistochemical analysis in distinguishing between metastasis and meningioma, especially when faced with ambiguous demarcation. Awareness of this occurrence is crucial, given that metastases might be the initial indication of an underlying tumor and it can impact the clinical management decisions.

Abstract Esophageal adenocarcinoma (EAC) is one of the deadliest tumor entities worldwide, with a 5-year survival rate of less than 25%. Unlike other tumor entities, personalized therapy options are rare, partly due to the lack of knowledge about specific subgroups. In this publication, we demonstrate a subgroup of patients with EAC in a large screening cohort of 826 patients, characterized by specific morphological and immunohistochemical features. This subgroup represents approximately 0.7% (6/826) of the total cohort. Morphological features of this subgroup show a striking clear cytoplasm of the tumour cells and the parallel existence of rare growth patterns like yolk sac-like differentiation and enteroblastic differentiation. Immunohistochemistry reveals expression of the fetal gut cell-like proteins Sal-like protein 4 (SALL4), claudin-6, and glypican 3. Interestingly, we find a correlation with alterations of SWI/SNF-complex associated genes, which are supposed to serve as tumor suppressor genes in various tumour entities. Our results suggest a possible implication of rare tumour subtypes in the WHO classification for EACs according to the classification for gastric cancer. Furthermore, claudin-6 positive tumors have shown promising efficacy of CAR T cell therapy in the recently published BNT-211-01 trial (NCT04503278). This represents a personalized therapeutic option for this tumor subtype.

Radiotherapy represents an essential treatment approach for esophageal cancer. Over recent years, immunotherapy combined with chemotherapy has become the first-line standard treatment for patients with advanced esophageal cancer. Several phase III studies on immunotherapy combined with radiotherapy for locally advanced esophageal cancer are currently underway. Sufficient evidence-based medical data are urgently needed to support the integration of immunotherapy and chemoradiotherapy as a new treatment strategy for patients with locally advanced esophageal cancer. This consensus, formulated based on the latest study results, in-depth research, and thorough discussions, provides a comprehensive set of recommendations. The document extensively covers treatment strategies and evaluation methods for radiotherapy combined with immunotherapy across patients with operable esophageal cancer, inoperable locally advanced esophageal cancer, and advanced esophageal cancer. Moreover, common complications and radiation-related issues associated with radiotherapy combined with immunotherapy are discussed, serving as clinical guidance. Our expert group comprised members from the Professional Committee of Radiation Oncology, China Anti-Cancer Association, the Branch of Radiation Oncology, Chinese Medical Association, and the Branch of Radiation Oncology Treatment Physician, Chinese Medical Doctor Association.

The incidence of esophageal adenocarcinoma (EAC) has surged by 600% in recent decades, with a dismal 5-year survival rate of just 15%. Barrett's esophagus (BE), affecting about 2% of the population, raises the risk of EAC by 40-fold. Despite this, the transcriptomic changes during the BE to EAC progression remain unclear. Our study addresses this gap through comprehensive transcriptomic profiling to identify key mRNA signatures and genomic alterations, such as gene fusions. We performed RNA-sequencing on BE and EAC tissues from 8 individuals, followed by differential gene expression, pathway and network analysis, and gene fusion prediction. We identified mRNA changes during the BE-to-EAC transition and validated our results with single-cell RNA-seq datasets. We observed upregulation of keratin family members in EAC and confirmed increased levels of keratin 14 (KRT14) using immunofluorescence. More differentiated BE marker genes are downregulated during progression to EAC, suggesting undifferentiated BE subpopulations contribute to EAC. We also identified several gene fusions absent in paired BE and normal esophagus but present in EAC. Our findings are critical for the BE-to-EAC transition and have the potential to promote early diagnosis, prevention, and improved treatment strategies for EAC. [ABSTRACT FROM AUTHOR]

Purpose: This updated umbrella review aimed to evaluate the evidence regarding the associations between dietary factors and the risks of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Methods: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify relevant studies. The quality of the included meta-analyses was evaluated using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2). For each association, the number of cases, random effects pooled effect size, 95% confidence intervals (CIs), heterogeneity, 95% prediction interval (PrI), small-study effect, and excess significance bias were recalculated to determine the evidence level. Results: We identified 33 meta-analyses describing 58 dietary factors associated with ESCC and 29 meta-analyses describing 38 dietary factors associated with EAC. There was convincing evidence regarding the association of 2 dietary factors (areca nut and high alcohol) with the risk of ESCC. There was highly suggestive evidence regarding the association of only 1 dietary factor (healthy pattern) with the risk of ESCC. There was suggestive evidence regarding the association of 11 dietary factors with the risk of ESCC, including fruit, citrus fruit, vegetables, pickled vegetables, maté tea, moderate alcohol, hot beverages and foods, hot tea, salt, folate, and vitamin B6. There was convincing evidence regarding the association of one dietary factor (vitamin B6) with the risk of EAC. There was suggestive evidence regarding the association of 4 dietary factors with the risk of EAC, including processed meat, dietary fibre, carbohydrate, and vitamin B12. The convincing evidence regarding the associations between dietary factors and the risks of ESCC and EAC remained robust in sensitivity analyses. Conclusions: This umbrella review highlighted convincing evidence regarding the associations of areca nut and high alcohol with a higher risk of ESCC. Additionally, an association between vitamin B6 and a decreased risk of EAC was observed. Further research is needed to examine the dietary factors with weak evidence regarding their associations with ESCC and EAC. [ABSTRACT FROM AUTHOR]

The z-line refers to the squamocolumnar junction which marks the transition between the normal stratified squamous epithelium of the distal esophagus and the columnar epithelium of the gastric cardia. An "irregular" z-line refers to an irregular appearing squamocolumnar junction characterized by the presence of columnar mucosa less than 1 cm in length that extends above the gastroesophageal junction. In contrast, Barrett's esophagus is diagnosed when columnar mucosa of at least 1 cm is seen in the distal esophagus extending above the gastroesophageal junction with biopsies demonstrating specialized intestinal metaplasia. Current guidelines recommend against taking routine biopsies from a normal or irregular z-line in the absence of visible abnormalities and advise against endoscopic surveillance in this patient population, in large part due to multiple studies demonstrating lack of progression to advanced neoplasia such as high-grade dysplasia or esophageal adenocarcinoma in patients with an irregular z-line. Despite these recommendations, a sizable number of patients without Barrett's esophagus undergo biopsies from the z-line and are subsequently recommended to have surveillance endoscopies. Furthermore, patients with an irregular z-line are often mislabelled as Barrett's esophagus resulting in significant downstream consequences including higher healthcare costs and reduced health-related quality of life. In this review, we highlight the importance of landmark identification of the distal esophagus and gastroesophageal junction at the time of endoscopy, share recommendations from current guidelines related to the z-line, examine rates of neoplastic progression in those with an irregular z-line, discuss consequences of routinely biopsying an irregular z-line, and highlight strategies on how to approach an irregular z-line if seen on endoscopy. A careful, high-quality endoscopic examination can help to identify visible abnormalities at the z-line, which, if present, should be targeted for biopsies to rule out dysplasia and neoplasia. [ABSTRACT FROM AUTHOR]

Simple Summary: Esophageal cancer, a highly lethal tumor, contributes to 5% of all cancer deaths, with its primary subtypes being esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). While most studies focus on ESCC, this study investigates EAC using single-cell RNA sequencing (scRNA-seq) to analyze CD45+ immune cells from tumors and matched non-tumor tissues in therapy-naïve patients. By examining the transcriptional profiles of these immune cells and the entire transcriptome in a cohort of 23 patients, this study identifies distinct transcriptional signatures. These signatures were used to stratify a large cohort of TCGA EAC patients, revealing strong associations with prognosis and clinical outcomes. The findings suggest that these transcriptional profiles can improve prognosis accuracy post-surgery and potentially guide effective therapies, including immunotherapy, for EAC patients. Esophageal cancer is a highly lethal malignancy, representing 5% of all cancer-related deaths. The two main subtypes are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). While most research has focused on ESCC, few studies have analyzed EAC for transcriptional signatures linked to diagnosis or prognosis. In this study, we utilized single-cell RNA sequencing and bulk RNA sequencing to identify specific immune cell types that contribute to anti-tumor responses, as well as differentially expressed genes (DEGs). We have characterized transcriptional signatures, validated against a wide cohort of TCGA patients, that are capable of predicting clinical outcomes and the prognosis of EAC post-surgery with efficacy comparable to the currently accepted prognostic factors. In conclusion, our findings provide insights into the immune landscape and therapeutic targets of EAC, proposing novel immunological biomarkers for predicting prognosis, aiding in patient stratification for post-surgical outcomes, follow-up, and personalized adjuvant therapy decisions. [ABSTRACT FROM AUTHOR]

Introduction: Over the past several decades, Europe and the United States have experienced a rapid increase in esophageal adenocarcinoma. Research and countermeasures against Barrett's esophagus, its precancerous lesion, are progressing. Because esophageal adenocarcinoma has an extremely poor prognosis when diagnosed in an advanced stage, recommendations for early cancer detection have been made based on the various proven etiological factors of Barrett's esophagus and the actual cancer risk of Barrett's esophagus. In recent years, there have been indications of an increase in esophageal adenocarcinoma in Japan, and a similar trend of cancer will occur shortly in other Asian countries. Consequently, Asian countries must implement similar countermeasures against Barrett's esophagus and esophageal adenocarcinoma, referencing the knowledge gained thus far in Europe and the United States. Areas covered: This review summarizes the latest findings on the etiologic factors of Barrett's esophagus and discusses the differences between Westerners and Asians. The current status of Barrett's esophagus in Japan and other Asian countries is also summarized. Expert opinion: The etiological factors and cancer incidence of Barrett's esophagus in Asia diverge somewhat from those observed in Europe and America. Therefore, it is imperative to implement measures that are tailored to the actual circumstances of Asian people. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is a pressing global health concern, ranking as the eighth most common cancer and the sixth leading cause for cancer-related deaths worldwide. Esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) are the two major histological types of esophageal cancer associated with distinct risk factors and geographical distributions. Unfortunately, the outcomes for both types of EC remain discouraging, with a five-year survival rate of less than 20% when diagnosed at advanced stages. Advanced endoscopic techniques have the potential to vastly enhance patient outcomes and impede the progression of pre-malignant lesions to cancer. However, low screening rates with endoscopy due to its invasive nature and high cost hinder its effectiveness. Despite extensive research on risk predictors, a significant number of cases still go undiagnosed, highlighting the need for improved screening techniques that can be implemented at the population level. To increase uptake, a shift towards minimally invasive, well-tolerated and cost-effective non-endoscopic technologies is crucial. The implementation of such devices in primary care settings, specifically targeting high-risk populations, can be a promising strategy. With early detection and enrollment in surveillance programs, there is hope for substantial improvement in morbidity and mortality rates through modern minimally invasive endoscopic and surgical techniques. [ABSTRACT FROM AUTHOR]

Objective: To analyze gene expression data of esophageal adenocarcinoma (EAC) in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases and clarify the relationship between the potential core genes and tumor lymphocyte infiltration in the EAC, and to provide the molecular targets for the diagnosis and treatment of EAC. Methods: The high-throughput chip datasets GSE13898, GSE26886, GSE74553, and GSE92396, including EAC and normal esophageal tissues, were downloaded from the GEO database by searching for “esophageal adenocarcinoma”. The limma package of R software was used to screen the differentially expressed genes (DEGs) in EAC tissue and esophageal normal tissue, and the common DEGs were obtained through Venn diagram. After the DEGs were analyzed by STRING database, the results were imported into Cytoscape software to screen the core genes and construct the protein-protein interaction (PPI) network. The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to verify the expression levels of core genes. The UALCAN and Kaplan-Meier Plotter databases were used to analyze the correlations between the core genes and prognosis and clinical data of the EAC patients. The Tumor Immune Estimation Resource (TIMER) database was used to analyze the relationship between core genes and tumor immune infiltration. Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were performed to analyze the positively correlated genes of core genes obtained from the LinkedOmics database. Results: A total of 340 DEGs were obtained from the intersection of DEGs from the four GEO datasets, including 127 upregulated genes and 213 downregulated genes. After screening with the STRING database and Cytoscape software, the key core genes with the highest scores were secreted phosphoprotein 1(SPP1) and transforming growth factor beta 1(TGFB1). The GEPIA database analysis results showed that compared with esophageal normal tissue, the expression levels of SPP1 and TGFB1 mRNA in cancer tissue were significantly increased (P<0. 01). The 1-year, 3-year, and 5-year overall survival of the EAC patients in SPP1 low expression group was higher than those in SPP1 high expression group (HR=10. 1, P<0. 05; HR=3. 09, P<0. 05; HR=2. 32, P<0. 05), and the 5-year overall survival of the EAC patients in TGFB1 low expression group was higher than that in TGFB1 high expression group (HR=2. 36, P<0. 05). The UALCAN database analysis results showed that compared with esophageal normal tissue, the expression levels of SPP1 and TGFB1 mRNA in cancer tissue of the EAC patients with stage Ⅱ-Ⅲ and N1-N2 lymph node metastasis were significantly increased (P<0. 01). The TIMER analysis results showed that the expression levels of SPP1 and TGFB1 mRNA in cancer tissue of the EAC patients were positively correlated with the infiltration of macrophages (r= 0. 353, P<0. 01; r=0. 187, P<0. 05) and dendritic cells (r=0. 236, P<0. 01; r=0. 221, P<0. 01). The GO and KEGG pathway enrichment analysis results showed that SPP1, TGFB1, and their top 50 positively correlated genes mainly participated in the biological processes such as cell migration, cell activity, and angiogenesis, and signaling pathways such as tumor proteoglycans, extracellular matrix (ECM)-receptor interaction, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT). Conclusion: SPP1 and TGFB1 are closely associated with clinical staging, lymph node metastasis, and overall survival of the EAC patients. High expressions of SPP1 and TGFB1 may lead to the infiltration of the macrophages and dendritic cells, and change the tumor microenvironment. SPP1 and TGFB1 may become new targets for the diagnosis and treatment of EAC. [ABSTRACT FROM AUTHOR]

We examined Fusobacterium nucreatum (F. nucleatum) and whole Fusobacterium species (Pan-fusobacterium) in non-neoplastic Barrett's esophagus (BE) from patients without cancer (n = 67; N group), with esophageal adenocarcinoma (EAC) (n = 27) and EAC tissue (n = 22). F. nucleatum was only detectable in 22.7% of EAC tissue. Pan-fusobacterium was enriched in EAC tissue and associated with aggressive clinicopathological features. Amount of Pan-fusobacterium in non-neoplastic BE was correlated with presence of hital hernia and telomere shortening. The result suggested potential association of Fusobacterium species in EAC and BE, featuring clinicpathological and molecular features. [ABSTRACT FROM AUTHOR]

Simple Summary: The accurate diagnosis of Barrett's esophagus (BE) and accurate grading of BE-associated dysplasia are essential for the optimal management of BE patients during surveillance. However, the diagnosis of BE may be missed, and the grading of BE–dysplasia has poor reproducibility and intra- and interobserver variability. Thus, well-defined biomarker testing remains indispensable. We conducted immunohistochemistry tests of a panel of biomarkers and discovered that MUC2 and TFF3 are specific diagnostic markers for BE. Moreover, the aberrant expressions of p53, p16, cyclin D1, Ki-67, beta-catenin, and MCM2 are significantly associated with LGD, HGD, and EAC histology with a high sensitivity and specificity and can be used to predict the risk of neoplastic changes and progression. Background: Barrett's esophagus (BE) is a pre-neoplastic condition associated with an increased risk of esophageal adenocarcinoma (EAC). The accurate diagnosis of BE and grading of dysplasia can help to optimize the management of patients with BE. However, BE may be missed and the accurate grading of dysplasia based on a routine histology has a considerable intra- and interobserver variability. Thus, well-defined biomarker testing remains indispensable. The aim of our study was to identify routinely applicable and relatively specific biomarkers for an accurate diagnosis of BE, as well as determining biomarkers to predict the risk of progression in BE–dysplasia. Methods: Retrospectively, we performed immunohistochemistry to test mucin 2(MUC2), trefoil factor 3 (TFF3), p53, p16, cyclin D1, Ki-67, beta-catenin, and minichromosome maintenance (MCM2) in biopsies. Prospectively, to identify chromosomal alterations, we conducted fluorescent in situ hybridization testing on fresh brush samples collected at the time of endoscopy surveillance. Results: We discovered that MUC2 and TFF3 are specific markers for the diagnosis of BE. Aberrant expression, including the loss and strong overexpression of p53, Ki-67, p16, beta-catenin, cyclin D1, and MCM2, was significantly associated with low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC histology, with a relatively high risk of neoplastic changes. Furthermore, the aberrant expressions of p53 and p16 in BE-indefinite dysplasia (IND) progressor cohorts predicted the risk of progression. Conclusions: Assessing the biomarkers would be a suitable adjunct to accurate BE histology diagnoses and improve the accuracy of BE–dysplasia grading, thus reducing interobserver variability, particularly of LGD and risk prediction. [ABSTRACT FROM AUTHOR]

Patients with early (T1) esophageal adenocarcinoma (EAC) are increasingly having definitive local therapy endoscopically. Endoscopic resection is not able to pathologically stage or treat lymph node metastasis (LNM). Accurate identification of patients having nodal metastasis is critical to select endoscopic therapy over surgery. This study aimed to define the risk of LNM in T1 EAC. A meta-analysis of studies of patients who underwent surgery and lymphadenectomy with assessment of LNM was performed according to PRISMA. Main outcome was probability of LNM in T1a and T1b disease. Secondary outcomes were risk factors for LNM and rate of LNM in submucosal T1b (SM1, SM2, and SM3) disease. Registered with PROSPERO (CRD42022341794). Twenty cohort studies involving 2264 patients with T1 EAC met inclusion criteria: T1a (857 patients) with 36 (4.2%) node positive and T1b (1407 patients) with 327 (23.2%) node positive. Subgroup analysis of T1b lesions was available in 10 studies (405 patients). Node positivity for SM1, SM2, and SM3 was 16.3%, 16.2%, and 29.4%, respectively. T1 substage (odds ratio [OR] 7.72, 95% confidence interval [CI] 4.45–13.38, P  < 0.01), tumor differentiation (OR 2.82, 95% CI 2.06–3.87, P  < 0.01), and lymphovascular invasion (OR 13.65, 95% CI 6.06–30.73, P  < 0.01) were associated with LNM. T1a disease demonstrated a 4.2% nodal metastasis rate and T1b disease a rate of 23.2%. Endoscopic therapy should be reserved for T1a disease and perhaps select T1b disease, which has a moderately high rate of nodal metastasis. There were inadequate data to stratify T1b SM disease into 'low-risk' and 'high-risk' based on tumor differentiation and lymphovascular invasion. [ABSTRACT FROM AUTHOR]

Current management of esophageal carcinoma (EC) involves combining different modalities, offering the opportunity of personalized strategies. This is particularly enticing in the geriatric population, where tailoring treatment modalities remains key to achieve good outcomes in terms of both quality of life and survival. Primary outcomes of our review included (1) evidence on short-term outcomes following esophagectomy, and (2) evidence on long-term outcomes following esophagectomy. Secondary review questions compared outcomes of (1) neoadjuvant treatment versus upfront surgery for locally advanced esophageal carcinoma, (2) endoscopic submucosal dissection versus esophagectomy for early esophageal carcinoma, and (3) definitive radiation with or without chemotherapy versus surgery. Twenty-six articles were included in the review for the main review questions. Our systematic review underscores the need for comprehensive geriatric evaluations to guide decision-making. Despite concerns about perioperative risks, well-selected older patients can derive survival benefits from surgical intervention. [ABSTRACT FROM AUTHOR]

The current staging system for esophageal adenocarcinoma only considers tumor grade in early tumors. The aim of this study was to evaluate the impact of tumor differentiation on response to neoadjuvant chemoradiotherapy and survival in patients with locally advanced esophageal adenocarcinoma. This was a multi-institution retrospective review of all patients with esophageal cancer who underwent neoadjuvant chemoradiotherapy followed by esophagectomy from January 2010 to December 2017. Response to neoadjuvant therapy and survival was compared between patients with well- or moderately differentiated (G1/2) tumors versus poorly differentiated (G3) tumors. There were 550 patients, 485 men (88.2%) and 65 women. The median age was 61 years, and the tumor was G1/2 in 288 (52.4%) and G3 in 262 patients. Overall clinical stage before neoadjuvant therapy was similar between groups. Pathologic complete response (pCR) was found in 87 patients (15.8%). The frequency of pCR was similar between groups, but residual disease in the esophagus and lymph nodes was significantly more likely with G3 tumors. Median follow-up was 63 months and absolute survival, overall survival, and disease-free survival were all significantly worse in patients with G3 tumors. Further, even with pCR, patients with G3 tumors had significantly worse survival. This study showed that response to neoadjuvant therapy was not affected by tumor differentiation. However, poor differentiation was associated with worse survival compared with patients with G1/2 tumors, even among those with pCR. These results suggest that poor differentiation should be considered as an added risk factor for clinical staging in patients with locally advanced esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Purpose of Review: Barrett's esophagus (BE) is the precursor of most Esophageal Adenocarcinomas (EACs) and progresses via the development of dysplasia. Hence BE screening is recommended by gastroenterology societies in patients with risk factors. Endoscopic surveillance enables the detection of dysplasia and early stage EAC, which can be treated successfully endoscopically, reducing the incidence and mortality of EAC. Despite these recommendations, only 10% of all EACs are detected in a surveillance program, and only a third or less of all BE cases are diagnosed. Recent Findings: While cost associated with endoscopic screening is a barrier to screening those with risk factors, non-endoscopic cell-collection devices combined with biomarkers, namely Cytosponge-TFF3 and EsophaCap/EsoChek-MDM, are effective alternatives that may allow cost-effective screening in this population. Current guidelines which recommend screening in only those with GERD and other risk factors have been found to be poorly sensitive for BE and EAC given the substantial prevalence of BE in those without GERD. Hence several prediction models to enable the identification of those at risk for BE/EAC with moderate accuracy have been developed. Summary: Future guidelines and risk prediction models for BE screening should include patients without GERD. BE prediction models encompassing multiple risk factors should be integrated into electronic health records to automatically identify patients at high risk. Cytosponge-TFF3 or EsophaCap/EsoChek-MDM, with subsequent diagnostic endoscopy in those with positive tests, can then be performed. Future studies to investigate whether this approach improves higher rates of BE/EAC screening and detection are warranted. [ABSTRACT FROM AUTHOR]

IntroductionEsophageal adenocarcinoma (EAC) remains a devastating disease and second line treatment options in the metastatic space are limited. Homologous recombination (HR) defects have been described in EAC in up to 40% of patients. Poly (ADP-ribose) polymerase (PARP)1 and PARP2 inhibitors have shown efficacy in HR defective prostate and ovarian cancers. Here, we describe the activity of the PARP inhibitor niraparib in metastatic EAC with HR defects.MethodsIn this single arm Simon two-stage Phase II study, we assessed the safety and efficacy of niraparib in patients with metastatic EAC previously treated with platinum containing chemotherapy harboring defective HR. Defective HR was defined as deleterious alterations in the following HR genes: BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1.Results14 patients were enrolled in this study. The trial was stopped early due to slow accrual. 3 patients did not have post-treatment scans because of rapid clinical decline. The overall response rate (ORR) (95% exact CI) was 0/11 = 0% (0%, 28.49%). The disease control rate (DCR) (95% exact CI) was 2/11 = 18.2% (2.3%, 51.8%). The median PFS was 1.8 months (95% CI = 1.0-3.7). The median OS for evaluable patients was 6.6 months (95% CI =2.7-11.4) and 5.7 months for all patients (95% CI =2.7-10.1). The most common adverse events seen were anemia, fatigue, and thrombocytopenia.ConclusionIn patients with metastatic EAC, single agent niraparib as second line therapy is not an effective option.

Esophageal adenocarcinoma (EAC) is a subtype of esophageal cancer with significant morbidity and mortality rates worldwide. Despite advancements in tumor models, the underlying cellular and molecular mechanisms driving EAC pathogenesis are still poorly understood. Therefore, gaining insights into these mechanisms is crucial for improving patient outcomes. Researchers have developed various models to better understand EAC and evaluate clinical management strategies. However, no single model fully recapitulates the complexity of EAC. Emerging technologies, such as patient-derived organoids and immune-competent mouse models, hold promise for personalized EAC research and drug development. In this review, we shed light on the various models for studying EAC and discuss their advantages and limitations.

BackgroundEsophageal cancer management lacks reliable response predictors to chemotherapy. In this study we evaluated the feasibility and accuracy of Biodynamic Imaging (BDI), a technology that employs digital holography as a rapid predictor of chemotherapy sensitivity in locoregional esophageal adenocarcinoma.MethodsPre-treatment endoscopic pinch biopsies were collected from patients with esophageal adenocarcinoma during standard staging procedures. BDI analyzed the tumor samples and assessed in vitro chemotherapy sensitivity. BDI sensitivity predictions were compared to patients’ pathological responses, the gold standard for determining clinical response, in the surgically treated subset (n=18).ResultBDI was feasible with timely tissue acquisition, collection, and processing in all 30 enrolled patients and successful BDI analysis in 28/29 (96%) eligible. BDI accurately predicted chemotherapy response in 13/18 (72.2%) patients using a classifier for complete, marked, and partial/no-response. BDI technology had 100% negative predictive value for complete pathological response hence identifying patients unlikely to respond to treatment.ConclusionBDI technology can potentially predict patients’ response to platinum chemotherapy. Additionally, this technology represents a promising step towards optimizing treatment strategies for esophageal adenocarcinoma patients by pre-emptively identifying non-responders to conventional platinum-based chemotherapy.

Abstract Background and Aim Various deep learning models, based on convolutional neural network (CNN), have been shown to improve the detection of early esophageal neoplasia in Barrett's esophagus. Vision transformer (ViT), derived from natural language processing, has emerged as the new state‐of‐the‐art for image recognition, outperforming predecessors such as CNN. This pilot study explores the use of ViT to classify the presence or absence of early esophageal neoplasia in endoscopic images of Barrett's esophagus. Methods A BO dataset of 1918 images of Barrett's esophagus from 267 unique patients was used. The images were classified as dysplastic (D‐BO) or non‐dysplastic (ND‐BO). A pretrained vision transformer model, ViTBase16, was used to develop our classifier models. Three ViT models were developed for comparison based on imaging modality: white‐light imaging (WLI), narrow‐band imaging (NBI), and combined modalities. Performance of each model was evaluated based on accuracy, sensitivity, specificity, confusion matrices, and receiver operating characteristic curves. Results The ViT models demonstrated the following performance: WLI‐ViT (Accuracy: 92%, Sensitivity: 82%, Specificity: 95%), NBI‐ViT (Accuracy: 99%, Sensitivity: 97%, Specificity: 99%), and combined modalities‐ViT (Accuracy: 93%, Sensitivity: 87%, Specificity: 95%). Combined modalities‐ViT showed greater accuracy (94% vs 90%) and sensitivity (80% vs 70%) compared with WLI‐ViT when classifying WLI images on a subgroup testing set. Conclusion ViT exhibited high accuracy in classifying the presence or absence of EON in endoscopic images of Barrett's esophagus. ViT has the potential to be widely applicable to other endoscopic diagnoses of gastrointestinal diseases.

Epithelial-mesenchymal transition (EMT) has been identified as a driver of therapy resistance, particularly in esophageal adenocarcinoma (EAC), where transforming growth factor beta (TGF-β) can induce this process. Inhibitors of TGF-β may counteract the occurrence of mesenchymal, resistant tumor cell populations following chemo(radio)therapy and improve treatment outcomes in EAC. Here, we aimed to identify predictive biomarkers for the response to TGF-β targeting. In vitro approximations of neoadjuvant treatment were applied to publicly available primary EAC cell lines. TGF-β inhibitors fresolimumab and A83–01 were employed to inhibit EMT, and mesenchymal markers were quantified via flow cytometry to assess efficacy. Our results demonstrated a robust induction of mesenchymal cell states following chemoradiation, with TGF-β inhibition leading to variable reductions in mesenchymal markers. The cell lines were clustered into responders and non-responders. Genomic expression profiles were obtained through RNA-seq analysis. Differentially expressed gene (DEG) analysis identified 10 positively- and 23 negatively-associated hub genes, which were bioinformatically identified. Furthermore, the correlation of DEGs with response to TGF-β inhibition was examined using public pharmacogenomic databases, revealing 9 positively associated and 11 negatively associated DEGs. Among these, ERBB2, EFNB1, and TNS4 were the most promising candidates. Our findings reveal a distinct gene expression pattern associated with the response to TGF-β inhibition in chemo(radiated) EAC. The identified DEGs and predictive markers may assist patient selection in clinical studies investigating TGF-β targeting.

A hyperechoic nodule in the liver has a broad differential; however, the vast majority are benign lesions. We report a case of a 29-year-old man with a history of anxiety and depression who presented to the hospital due to a 12-day history of epigastric pain with radiation to the back, fevers, and night sweats. Initial imaging revealed a small hyperechoic nodule on the liver, originally believed to be an abscess. Image-guided aspiration was attempted but no fluid could be drained. An endoscopic ultrasound was pursued to further evaluate the lesion and obtain a biopsy. An ulcerated esophageal mass was incidentally identified on endoscopy. Hepatic and esophageal biopsies demonstrated moderately differentiated adenocarcinoma, with esophageal adenocarcinoma as the primary source. This case highlights an interesting presentation for the rare occurrence of metastatic esophageal adenocarcinoma in a young, healthy individual without identifiable risk factors. KEY POINTS: Hepatic hyperechoic lesions have a vast differential and require a broad workup to identify the true etiology. The incidence of esophageal cancers is steadily increasing worldwide, with projections showing dramatic increases over the next 20 years. Esophageal cancers carry a poor prognosis, with worse outcomes in younger populations. Current guidelines do not include any endoscopy screening recommendations for younger populations, so clinicians must develop strong clinical judgment when evaluating reflux symptoms. [ABSTRACT FROM AUTHOR]