Vagal Sparing Gastrectomy: A Systematic Review and Meta-Analysis.

INTRODUCTION: Radical gastrectomy is associated with significant functional complications. In appropriate patients may be amenable to less invasive resection aimed at preserving the vagal trunks. The aim of this systematic review and meta-analysis was to assess the functional consequences and oncological safety of vagal sparing gastrectomy (VSG) compared to conventional non-vagal sparing gastrectomy (CG). METHODS: A systematic review of four databases in accordance with PRISMA guidelines was undertaken for studies published between January 1, 1990, and December 15, 2021, comparing patients who underwent VSG to CG. We meta-analysed the following outcomes: operative time, blood loss, nodal yield, days to flatus, body weight changes, as well as the incidence of post-operative cholelithiasis, diarrhoea, delayed gastric emptying, and dumping syndrome. RESULTS: Thirty studies were included in the meta-analysis with a selection of studies qualitatively analysed. VSG was associated with a lower rate of cholelithiasis (OR: 0.25, 95% CI: 0.15-0.41, p < 0.010) and early dumping syndrome (OR: 0.42, 95% CI: 0.21-0.86; p = 0.02), less blood loss (mean difference [MD]: -51 mL, 95% CI: -89.11 to -12.81 mL, p = 0.009), less long-term weight loss (MD: 2.03%, 95% CI: 0.31-3.76%, p = 0.02) and a faster time to flatus (MD: -0.42 days, 95% CI: -0.48 to 0.36, p < 0.001). There was no significant difference in nodal harvest, overall survival, and all other endpoints. CONCLUSION: VSG significantly reduces the incidence of post-operative cholelithiasis and dumping syndrome, decreases weight loss, and facilitates an earlier return of gut motility. Although technically more challenging, VSG should be considered for prophylactic surgery.

Determining the learning curve of minimally invasive antireflux surgery: systematic review, meta-analysis, and meta-regression.

The rapid uptake of minimally invasive antireflux surgery has led to interest in learning curves for this procedure. This study ascertains the learning curve in laparoscopic and robotic-assisted antireflux surgery. A systematic review of the literature pertaining to learning curves in minimally invasive fundoplication with or without hiatal hernia repair was performed using PubMed, Medline, Embase, Web of Science, and Cochrane Library databases. A meta-regression analysis was undertaken to identify the number of cases to achieve surgical proficiency, and a meta-analysis was performed to compare outcomes between cases that were undertaken during a surgeon's learning phase and experienced phase. Twenty-five studies met the eligibility criteria. A meta-regression analysis was performed to quantitatively investigate the trend of number of cases required to achieve surgical proficiency from 1996 to present day. Using a mixed-effects negative binomial regression model, the predicted learning curve for laparoscopic and robotic-assisted antireflux surgery was found to be 24.7 and 31.1 cases, respectively. The meta-analysis determined that surgeons in their learning phase may experience a moderately increased rate of conversion to open procedure (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.28, 4.64), as well as a slightly increased rate of intraoperative complications (OR 1.60; 95% CI 1.08, 2.38), postoperative complications (OR 1.98; 95% CI 1.36, 2.87), and needing reintervention (OR 1.64; 95% CI 1.16, 2.34). This study provides an insight into the expected caseload to be competent in performing antireflux surgery. The discrepancy between outcomes during and after the learning curve for antireflux surgery suggests a need for close proctorship for learning surgeons.

Understanding Potentially Preventable Mortality Following Oesophago-Gastric Cancer Surgery: Analysis of a National Audit of Surgical Mortality.

INTRODUCTION: At a national level, understanding preventable mortality after oesophago-gastric cancer surgery can direct quality-improvement efforts. Accordingly, utilizing the Australian and New Zealand Audit of Surgical Mortality (ANZASM), we aimed to: (1) determine the causes of death following oesophago-gastric cancer resections in Australia, (2) quantify the proportion of potentially preventable deaths, and (3) identify clinical management issues contributing to preventable mortality. METHODS: All in-hospital mortalities following oesophago-gastric cancer surgery from 1 January 2010 to 31 December 2020 were analysed using ANZASM data. Potentially preventable and non-preventable cases were compared. Thematic analysis with a data-driven approach was used to classify clinical management issues. RESULTS: Overall, 636 complications and 123 clinical management issues were identified in 105 mortalities. The most common causes of death were cardio-respiratory in aetiology. Forty-nine (46.7%) deaths were potentially preventable. These cases were characterized by higher rates of sepsis (59.2% vs 33.9%, p = 0.011), multiorgan dysfunction syndrome (40.8% vs 25.0%, p = 0.042), re-operation (63.3% vs 41.1%, p = 0.031) and other complications compared with non-preventable mortality. Potentially preventable mortalities also had more clinical management issues per patient [median (IQR): 2 (1-3) vs 0 (0-1), p < 0.001), which adversely impacted preoperative (30.6% vs 7.1%, p = 0.002), intraoperative (18.4% vs 5.4%, p = 0.037) and postoperative (51.0% vs 17.9%, p < 0.001) care. Thematic analysis highlighted recurrent areas of deficiency with preoperative, intraoperative and postoperative patient management. CONCLUSIONS: Almost 50% of deaths following oesophago-gastric cancer resections were potentially preventable. These were characterized by higher complication rates and clinical management issues. We highlight recurrent themes in patient management to improve future quality of care.

Tumor-Infiltrating Neutrophils after Neoadjuvant Therapy are Associated with Poor Prognosis in Esophageal Cancer.

BACKGROUND: In esophageal cancer (EC), there is a paucity of knowledge regarding the interplay between the tumor immune microenvironment and response to neoadjuvant treatment and, therefore, which factors may influence outcomes. Thus, our goal was to investigate the changes in the immune microenvironment with neoadjuvant treatment in EC by assessing the expression of immune related genes and their association with prognosis. METHODS: We examined the transcriptome of paired pre- and post-neoadjuvant treated EC specimens. Based on these findings, we validated the presence of tumor-infiltrating neutrophils using CD15+ immunohistochemistry in a discovery cohort of patients with residual pathologic disease. We developed a nomogram as a predictor of progression-free survival (PFS) incorporating the variables CD15+ cell count, tumor regression grade, and tumor grade. RESULTS: After neoadjuvant treatment, there was an increase in genes related to myeloid cell differentiation and a poor prognosis associated with high neutrophil (CD15+) counts. Our nomogram incorporating CD15+ cell count was predictive of PFS with a C-index of 0.80 (95% confidence interval [CI] 0.68-0.9) and a concordance probability estimate (CPE) of 0.77 (95% CI 0.69-0.86), which indicates high prognostic ability. The C-index and CPE of the validation cohort were 0.81 (95% CI 0.69-0.91) and 0.78 (95% CI 0.7-0.86), respectively. CONCLUSIONS: Our nomogram incorporating CD15+ cell count can potentially be used to identify patients at high risk of recurrent disease and thus stratify patients who will benefit most from adjuvant treatment.

Para-conduit diaphragmatic hernia following esophagectomy-the new price of minimally invasive surgery?

Esophageal Cancer is the seventh commonest cancer worldwide with poor overall survival. Significant morbidity related to open esophagectomy has driven practice toward hybrid, totally minimally invasive and robotic procedures. With the increase in minimally invasive approaches, it has been suggested that there might be an increased incidence of subsequent para-conduit diaphragmatic hernia. To assess the incidence, modifiable risk factors and association with operative approach of this emerging complication, we evaluated outcomes following esophagectomy from two Australian Centers. Prospectively collected databases were examined to identify patients who developed versus did not develop a para-conduit hernia. Patient characteristics, disease factors, treatment factors, operative and post-operative factors were compared for these two groups. A total of 24 of 297 patients who underwent esophagectomy were diagnosed with a symptomatic para-conduit diaphragmatic hernia (8.1%). The significant risk factor for hernia was a minimally invasive abdominal approach (70.8% vs. 35.5%; P = 0.004, odds ratio = 12.876, 95% CI 2.214-74.89). Minimally invasive thoracic approaches were not associated with increased risk. Minimally invasive abdominal approaches to esophagectomy doubled the risk of developing a para-conduit diaphragmatic hernia. Effective operative solutions to address this complication are required.

Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma.

OBJECTIVE: To explore the clinical utility of circulating tumor DNA (ctDNA) in esophageal adenocarcinoma (EAC) by developing a cost-effective and rapid technique utilising targeted amplicon sequencing. SUMMARY OF BACKGROUND DATA: Emerging evidence suggests that levels of ctDNA in the blood can be used to monitor treatment response and in the detection of disease recurrence in various cancer types. Current staging modalities for EAC such as computerised tomography of the chest/abdomen/pelvis (CT) and positron emission tomography (PET) do not reliably detect occult micro-metastatic disease, the presence of which signifies a poor prognosis. After curative-intent treatment, some patients are still at high risk of recurrent disease, and there is no widely accepted optimal surveillance tool for patients with EAC. METHODS: Sixty-two patients with EAC were investigated for the presence of ctDNA using a tumor-informed approach. We designed a custom targeted amplicon sequencing panel of target specific primers covering mutational foci in 9 of the most commonly mutated genes in EAC. Serial blood samples were taken before and after neoadjuvant treatment (NAT), and during surveillance. RESULTS: Somatic mutations were detected in pre-treatment biopsy samples of 55 out of 62 (89%) EAC patients. Mutations in TP53 (80%) were the most common. Out of these 55 patients, 20 (36%) had detectable ctDNA at baseline. The majority (90%) of patients with detectable ctDNA had either locally advanced tumors, nodal involvement or metastatic disease. In patients with locally advanced tumors, disease free survival (DFS) was more accurately stratified using pre-treatment ctDNA status [HR 4.34 (95% CI 0.93-20.21); P = 0.05] compared to nodal status on PET-CT. In an exploratory subgroup analysis, patients who are node negative but ctDNA positive have inferior DFS [HR 11.71 (95% CI 1.16-118.80) P = 0.04]. In blood samples taken before and following NAT, clearance of ctDNA after NAT was associated with a favourable response to treatment. Furthermore, patients who are ctDNA positive during post-treatment surveillance are at high risk of relapse. CONCLUSIONS: Our study shows that ctDNA has potential to provide additional prognostication over conventional staging investigation such as CT and PET. It may also have clinical utility in the assessment of response to NAT and as a biomarker for the surveillance of recurrent disease.

Increased risk of diaphragmatic herniation following esophagectomy with a minimally invasive abdominal approach.

OBJECTIVE: Diaphragmatic herniation is a rare complication following esophagectomy, associated with risks of aspiration pneumonia, bowel obstruction, and strangulation. Repair can be challenging due to the presence of the gastric conduit. We performed this systematic review and meta-analysis to determine the incidence and risk factors associated with diaphragmatic herniation following esophagectomy, the timing and mode of presentation, and outcomes of repair. METHODS: A systematic search using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was performed using four major databases. A meta-analysis of diaphragmatic herniation incidence following esophagectomies with a minimally invasive abdominal (MIA) approach compared with open esophagectomies was conducted. Qualitative analysis was performed for tumor location, associated symptoms, time to presentation, and outcomes of postdiaphragmatic herniation repair. RESULTS: This systematic review consisted of 17,052 patients from 32 studies. The risk of diaphragmatic herniation was 2.74 times higher in MIA esophagectomy compared with open esophagectomy, with pooled incidence of 6.0% versus 3.2%, respectively. Diaphragmatic herniation was more commonly seen following surgery for distal esophageal tumors. Majority of patients (64%) were symptomatic at diagnosis. Presentation within 30 days of operation occurred in 21% of cases and is twice as likely to require emergent repair with increased surgical morbidity. Early diaphragmatic herniation recurrence and cardiorespiratory complications are common sequelae following hernia repair. CONCLUSIONS: In the era of MIA esophagectomy, one has to be cognizant of the increased risk of diaphragmatic herniation and its sequelae. Failure to recognize early diaphragmatic herniation can result in catastrophic consequences. Increased vigilance and decreased threshold for imaging during this period is warranted.

A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset of NUTM1-rearranged tumors.

Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.

2D-quantitative structure-activity relationships model using PLS method for anti-malarial activities of anti-haemozoin compounds.

BACKGROUND: Emergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial activity against the resistant strains. One of the most promising therapeutic targets of anti-malarial agents related to food vacuole of malaria parasite is haemozoin, a product formed by the parasite through haemoglobin degradation. METHODS: With this in mind, this study developed two-dimensional-quantitative structure-activity relationships (QSAR) models of a series of 21 haemozoin inhibitors to explore the useful physicochemical parameters of the active compounds for estimation of anti-malarial activities. The 2D-QSAR model with good statistical quality using partial least square method was generated after removing the outliers. RESULTS: Five two-dimensional descriptors of the training set were selected: atom count (a_ICM); adjacency and distance matrix descriptor (GCUT_SLOGP_2: the third GCUT descriptor using atomic contribution to logP); average total charge sum (h_pavgQ) in pKa prediction (pH = 7); a very low negative partial charge, including aromatic carbons which have a heteroatom-substitution in "ortho" position (PEOE_VSA-0) and molecular descriptor (rsynth: estimating the synthesizability of molecules as the fraction of heavy atoms that can be traced back to starting material fragments resulting from retrosynthetic rules), respectively. The model suggests that the anti-malarial activity of haemozoin inhibitors increases with molecules that have higher average total charge sum in pKa prediction (pH = 7). QSAR model also highlights that the descriptor using atomic contribution to logP or the distance matrix descriptor (GCUT_SLOGP_2), and structural component of the molecules, including topological descriptors does make for better anti-malarial activity. CONCLUSIONS: The model is capable of predicting the anti-malarial activities of anti-haemozoin compounds. In addition, the selected molecular descriptors in this QSAR model are helpful in designing more efficient compounds against the P. falciparum 3D7A strain.

GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma.

Efficacious therapeutic approaches are urgently needed to improve outcomes in patients with oesophageal adenocarcinoma (OAC). However, oncogenic drivers amenable to targeted therapy are limited and their functional characterisation is essential. Among few targeted therapies available, anti-human epidermal growth factor receptor 2 (HER2) therapy showed only modest benefit for patients with OAC. Herein, we investigated the potential oncogenic role of growth factor receptor bound protein 7 (GRB7), which is reported to be co-amplified with HER2 (ERBB2) in OAC. GRB7 was highly expressed in 15% of OAC tumours, not all of which could be explained by co-amplification with HER2, and was associated with a trend for poorer overall survival. Knockdown of GRB7 decreased proliferation and clonogenic survival, and induced apoptosis. Reverse phase protein array (RPPA) analyses revealed a role for PI3K, mammalian target of rapamycin (mTOR), MAPK, and receptor tyrosine kinase signalling in the oncogenic action of GRB7. Furthermore, the GRB7 and HER2 high-expressing OAC cell line Eso26 showed reduced cell proliferation upon GRB7 knockdown but was insensitive to HER2 inhibition by trastuzumab. Consistent with this, GRB7 knockdown in vivo with an inducible shRNA significantly inhibited tumour growth in cell line xenografts. HER2 expression did not predict sensitivity to trastuzumab, with Eso26 xenografts remaining refractory to trastuzumab treatment. Taken together, our study provides strong evidence for an oncogenic role for GRB7 in OAC and suggests that targeting GRB7 may be a potential therapeutic strategy for this cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Clinical pathways and outcomes of patients with Barrett's esophagus in tertiary care settings: a prospective longitudinal cohort study in Australia, 2008-2016.

BACKGROUND: Clinical services for Barrett's esophagus have been rising worldwide including Australia, but little is known of the long-term outcomes of such patients. Retrospective studies using data at baseline are prone to both selection and misclassification bias. We investigated the clinical characteristics and outcomes of Barrett's esophagus patients in a prospective cohort. METHODS: We recruited patients diagnosed with Barrett's esophagus in tertiary settings across Australia between 2008 and 2016. We compared baseline and follow-up epidemiological and clinical data between Barrett's patients with and without dysplasia. We calculated age-adjusted incidence rates and estimated minimally and fully adjusted hazard ratios (HR) to identify those clinical factors related to disease progression. RESULTS: The cohort comprised 268 patients with Barrett's esophagus (median follow-up 5 years). At recruitment, 224 (84%) had no dysplasia, 44 (16%) had low-grade or indefinite dysplasia (LGD/IND). The age-adjusted incidence of esophageal adenocarcinoma (EAC) was 0.5% per year in LGD/IND compared with 0.1% per year in those with no dysplasia. Risk of progression to high-grade dysplasia/EAC was associated with prior LGD/IND (fully adjusted HR 6.55, 95% confidence interval [CI] 1.96-21.8) but not long-segment disease (HR 1.03, 95%CI 0.29-3.58). CONCLUSIONS: These prospective data suggest presence of dysplasia is a stronger predictor of progression to cancer than segment length in patients with Barrett's esophagus.

Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours.

Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common cooperative changes required for tumourigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET, and MAX. Using whole exome sequencing and high-density single-nucleotide polymorphism arrays, we analysed two to four primary tumours from each patient. We also applied multi-region sampling, to assess intratumoural heterogeneity and clonal evolution, in two cases involving paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Palliative care in general practice: GP integration in caring for patients with advanced cancer.

BACKGROUND: Patients with advanced cancer often desire home-based care, placing general practitioners (GPs) at the centre of complex clinical situations. The objective of this article was to determine GPs' needs when providing home-based palliative care in collaboration with existing palliative care services. METHODS: A survey of GPs was conducted to determine knowledge, skills and confidence in providing community-based palliative care. RESULTS: Of the 56 respondents, 82% reported that they were involved in palliative management of at least one cancer patient in the previous year. A significant number of GPs (31%) lacked confidence in providing this care because of patient complexity, inadequate training and insufficient resources. Other barriers included poor communication from specialists and treating teams. Factors facilitating provision of home-based palliative care were community palliative care services and links to hospital-based palliative care teams. DISCUSSION: This survey highlights the importance of support and resources to empower GPs to confidently provide home-based palliative care for patients with advanced cancer.

Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient-Derived Tumor Xenografts.

BACKGROUND: Recently, there has been an increase in the availability of targeted molecular therapies for cancer treatment. The application of these approaches to esophageal cancer, however, has been hampered by the relative lack of appropriate models for preclinical testing. Patient-derived tumor xenograft (PDTX) models are gaining popularity for studying many cancers. Unfortunately, it has proven difficult to generate xenografts from esophageal cancer using these models. The purpose of this study was to improve the engraftment efficiency of esophageal PDTXs. METHODS: Fresh pieces of esophageal tumors obtained from endoscopic biopsies or resected specimens were collected from 23 patients. The tumors were then coated in Matrigel and transplanted in immunocompromised mice subcutaneously (n = 6) and/or using a novel implantation technique whereby the tumor is placed in a dorsal intramuscular pocket (n = 18). They are then monitored for engraftment. RESULTS: With the novel intramuscular technique, successful engraftment was achieved for all 18 patient tumors. Among these PDTXs, 13 recapitulated the original patient tumors with respect to degree of differentiation, molecular and genetic profiles, and chemotherapeutic response. Lymphomatous transformation was observed in the other five PDTXs. Successful engraftment was achieved for only one of six patient tumors using the classic subcutaneous approach. DISCUSSION: We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer.

Incremental diagnostic utility of gastric distension FDG PET/CT.

PURPOSE: To assess the diagnostic utility of gastric distension (GD) FDG PET/CT in both patients with known gastric malignancy and those not known to have gastric malignancy but with incidental focal FDG uptake in the stomach. METHODS: This retrospective analysis included 88 patients who underwent FDG PET/CT following GD with hyoscine N-butylbromide (Buscopan®) and water ingestion as part of routine clinical evaluation between 2004 and 2014. FDG PET/CT scans before and after GD were reported blinded to the patient clinical details in 49 patients undergoing pretreatment staging of gastric malignancy and 39 patients who underwent GD following incidental suspicious gastric uptake. The PET findings were validated by a composite clinical standard. RESULTS: In the 49 patients undergoing pretreatment staging of gastric malignancy, GD improved PET detection of the primary tumour (from 80 % to 90 %). PET evaluation of tumour extent was concordant with endoscopic/surgical reports in 31 % (interpreter 1) and 45 % (interpreter 2) using pre-GD images and 73 % and 76 % using GD images. Interobserver agreement also improved with GD (κ = 0.29 to 0.69). Metabolic and morphological quantitative analysis demonstrated a major impact of GD in normal gastric wall but no significant effect in tumour, except a minor increase in SUV related to a delayed acquisition time. The tumour to normal stomach SUVmax ratio increased from 3.8 ± 2.9 to 9.2 ± 8.6 (mean ± SD) with GD (p < 0.0001), facilitating detection and improved assessment of the primary tumour. In 25 (64 %) of the 39 patients with incidental suspicious gastric uptake, acquisition after GD correctly excluded a malignant process. In 10 (71 %) of the remaining 14 patients with persistent suspicious FDG uptake despite GD, malignancy was confirmed and in 3 (21 %) an active but benign pathology was diagnosed. CONCLUSION: GD is a simple way to improve local staging with FDG PET in patients with gastric malignancy. In the setting of incidental suspicious gastric uptake, GD is also an effective tool for ruling out malignancy and leads to the avoidance of unnecessary endoscopy.

The Genetics of Barrett's Esophagus: A Familial and Population-Based Perspective.

Barrett's esophagus (BE) is intestinal metaplasia of the lower esophagus and a precursor lesion for esophageal adenocarcinoma (EAC). Both are important health issues as they have rising incidences in the Western world. Improving the management of BE relies on understanding the underlying biology of this disease, but the exact biological mechanisms have been difficult to determine. BE is generally thought to be an acquired condition that develops secondarily to chronic gastroesophageal reflux. However, multiple reports of familial clustering of patients with BE and/or EAC suggest a possible inherited predisposition to BE may be driving this condition, at least in a subset of patients. Identifying the genetic variants that predispose to BE in these families would open up the possibility for blood-based screening tests that could inform decision-making in regard to surveillance strategies, particularly for relatives of patients with BE and/or EAC. Perhaps more importantly, understanding the genetic mechanisms that predispose to BE may provide valuable insights into the biology of this condition and potentially identify novel targets for therapeutic intervention. Here we review the current evidence for a genetic predisposition to BE and discuss the potential implications of these findings.