Advances in Screening for Barrett Esophagus and Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC), the primary form of esophageal cancer in the United States, is a lethal cancer with exponentially increasing incidence. Screening for Barrett esophagus (BE), the only known precursor to EAC, followed by endoscopic surveillance to detect dysplasia and early-stage EAC and subsequent endoscopic treatment (to prevent progression of dysplasia to EAC and to treat early-stage EAC effectively) is recommended by several society guidelines. Sedated endoscopy (the primary current tool for BE screening) is both invasive and expensive, limiting its widespread use. In this review, we aim to provide a comprehensive review of recent innovations in the nonendoscopic detection of BE and EAC. These include swallowable cell sampling devices combined with protein and epigenetic biomarkers (which are now guideline endorsed as alternatives to sedated endoscopy), tethered capsule endomicroscopy, emerging peripheral blood-sampled molecular biomarkers, and exhaled volatile organic compounds. We also summarize progress and challenges in assessing BE and EAC risk, which is an important complementary component of the process for the clinical implementation of these innovative nonendoscopic tools, and propose a new paradigm for the strategy to reduce EAC incidence and mortality.

Revisiting Proton Pump Inhibitors as Chemoprophylaxis Against the Progression of Barrett's Esophagus.

PURPOSE OF REVIEW: Barrett's esophagus (BE) is associated with chronic gastroesophageal reflux disease and is a known precursor to esophageal adenocarcinoma. While endoscopic surveillance strategies and the role for endoscopic eradication therapy have been well established, there has been much interest in identifying chemopreventive agents to disrupt or halt the metaplasia-dysplasia-carcinoma sequence in patients with BE. RECENT FINDINGS: No pharmacological agent has held more hope in reducing the risk of neoplastic progression in BE than proton pump inhibitors (PPIs). However, data supporting PPIs for chemoprevention have largely been from observational cohort and case-control studies with mixed results. In this review, we revisit the literature and highlight the role of PPIs in patients with BE as it pertains to chemoprophylaxis against the progression of BE to dysplasia and esophageal adenocarcinoma.

Decreased Risk of Esophageal Adenocarcinoma After Gastric Bypass Surgery in a Cohort Study From 3 Nordic Countries.

OBJECTIVE: The objective of this study was to test the hypothesis that bariatric surgery decreases the risk of esophageal and cardia adenocarcinoma. BACKGROUND: Obesity is strongly associated with esophageal adenocarcinoma and moderately with cardia adenocarcinoma, but whether weight loss prevents these tumors is unknown. METHODS: This population-based cohort study included patients with an obesity diagnosis in Sweden, Finland, or Denmark. Participants were divided into a bariatric surgery group and a nonoperated group. The incidence of esophageal and cardia adenocarcinoma (ECA) was first compared with the corresponding background population by calculating standardized incidence ratios (SIR) with 95% CIs. Second, the bariatric surgery group and the nonoperated group were compared using multivariable Cox regression, providing hazard ratios (HR) with 95% CI, adjusted for sex, age, comorbidity, calendar year, and country. RESULTS: Among 748,932 participants with an obesity diagnosis, 91,731 underwent bariatric surgery, predominantly gastric bypass (n=70,176; 76.5%). The SIRs of ECA decreased over time after gastric bypass, from SIR=2.2 (95% CI, 0.9-4.3) after 2 to 5 years to SIR=0.6 (95% CI, <0.1-3.6) after 10 to 40 years. Gastric bypass patients were also at a decreased risk of ECA compared with nonoperated patients with obesity [adjusted HR=0.6, 95% CI, 0.4-1.0 (0.98)], with decreasing point estimates over time. Gastric bypass was followed by a strongly decreased adjusted risk of esophageal adenocarcinoma (HR=0.3, 95% CI, 0.1-0.8) but not of cardia adenocarcinoma (HR=0.9, 95% CI, 0.5-1.6), when analyzed separately. There were no consistent associations between other bariatric procedures (mainly gastroplasty, gastric banding, sleeve gastrectomy, and biliopancreatic diversion) and ECA. CONCLUSIONS: Gastric bypass surgery may counteract the development of esophageal adenocarcinoma in morbidly obese individuals.

Effect of Helicobacter pylori Eradication Therapy on the Incidence of Noncardia Gastric Adenocarcinoma in a Large Diverse Population in the United States.

BACKGROUND & AIMS: High-quality data regarding the effect of Helicobacter pylori eradication on the risk of noncardia gastric adenocarcinoma (NCGA) remain limited in the United States. We investigated the incidence of NCGA after H pylori eradication therapy in a large, community-based US population. METHODS: We performed a retrospective cohort study of Kaiser Permanente Northern California members who underwent testing and/or treatment for H pylori between 1997 and 2015 and were followed through December 31, 2018. The risk of NCGA was evaluated using the Fine-Gray subdistribution hazard model and standardized incidence ratios. RESULTS: Among 716,567 individuals with a history of H pylori testing and/or treatment, the adjusted subdistribution hazard ratios and 95% confidence intervals of NCGA for H pylori-positive/untreated and H pylori-positive/treated individuals were 6.07 (4.20-8.76) and 2.68 (1.86-3.86), respectively, compared with H pylori-negative individuals. When compared directly with H pylori-positive/untreated individuals, subdistribution hazard ratios for NCGA in H pylori-positive/treated were 0.95 (0.47-1.92) at <8 years and 0.37 (0.14-0.97) ≥8 years of follow-up. Compared with the Kaiser Permanente Northern California general population, standardized incidence ratios (95% confidence interval) of NCGA steadily decreased after H pylori treatment: 2.00 (1.79-2.24) ≥1 year, 1.01 (0.85-1.19) ≥4 years, 0.68 (0.54-0.85) ≥7 years, and 0.51 (0.38-0.68) ≥10 years. CONCLUSION: In a large, diverse, community-based population, H pylori eradication therapy was associated with a significantly reduced incidence of NCGA after 8 years compared with no treatment. The risk among treated individuals became lower than the general population after 7 to 10 years of follow-up. The findings support the potential for substantial gastric cancer prevention in the United States through H pylori eradication.

Surveillance in Barrett's Esophagus: Challenges, Progress, and Possibilities.

Endoscopic surveillance of Barrett's esophagus, aiming to detect prevalent dysplasia and adenocarcinoma, followed by effective endoscopic treatment, is an integral part of the esophageal adenocarcinoma prevention paradigm. However, several limitations, such as the subtle appearance of dysplasia, sampling error (inherent in current surveillance protocols), and noncompliance with surveillance recommendations, lead to missed dysplasia and neoplasia, reducing the effectiveness of surveillance as currently practiced. Careful endoscopic assessment with high-resolution white-light endoscopy, dye-based or electronic chromoendoscopy, and comprehensive sampling of the BE mucosa, remains the cornerstone of endoscopic surveillance. Emerging innovations in this area span the gamut of more efficient sampling methods, advanced imaging tools, artificial intelligence, and molecular marker-powered approaches as adjuncts, to identify prevalent and predict incident dysplasia or adenocarcinoma. Development and implementation of validated quality indicators will allow additional advancement of this critical field. These approaches will hopefully enable efficient and effective cancer prevention and treatment.

Diet quality and risk of gastric adenocarcinoma: The Multiethnic Cohort.

BACKGROUND: Certain dietary patterns (i.e., low intake of fruit/vegetables and high intake of salt and processed meats) have been associated with the risk of gastric cancer. However, it is unclear whether overall diet quality assessed by predefined indices that consider the complexity of dietary intake is associated with gastric cardia and distal adenocarcinoma. OBJECTIVES: To examine the association of a variety of diet indices with the risk of gastric cardia and distal adenocarcinoma and assess whether there are any subgroups that may benefit from better diets to reduce the risk of gastric adenocarcinoma. METHODS: Dietary indices of interest included the Alternative Healthy Index (AHEI)-2010, Healthy Eating Index (HEI)-2015, the Dietary Approach to Stop Hypertension, alternate Mediterranean diet (aMED), and the energy-adjusted Dietary Inflammatory Index. RESULTS: After an average follow-up time of 19.2 years, there were 836 incident cases of gastric distal adenocarcinoma and 207 cases of gastric cardia adenocarcinoma. We did not observe any significant associations between the dietary indices and gastric cancer for either anatomic site. Among former aspirin users, we observed an inverse association between aMED with distal cancer (HRQ5 vs. Q1: 0.64; 95% CI: 0.33, 1.23; P-trend = 0.03). Never smokers, who showed high-quality diet according to AHEI-2010, exhibited a 40% decreased risk of gastric distal cancer compared with those with the poorest-quality AHEI-2010 diet (HRQ5 vs. Q1: 0.60; 95% CI: 0.41, 0.88; P-trend = 0.08). CONCLUSIONS: In a multiethnic population, we did not observe overall significant associations between these dietary quality indices and risk of gastric cancer. However, among former aspirin users and never smokers, there could be a reduction of gastric distal adenocarcinoma risk with a higher adherence to a Mediterranean diet.

Barrett Esophagus: Rapid Evidence Review.

Barrett esophagus is a premalignant change of the esophagus; however, malignant transformation to esophageal adenocarcinoma is rare in patients without dysplasia. Barrett esophagus is estimated to affect up to 5.6% of the U.S. population. Risk factors for Barrett esophagus include gastroesophageal reflux disease, obesity, age older than 50 years, male sex, tobacco use, and a family history of Barrett esophagus or esophageal adenocarcinoma. Patients who experience chronic gastroesophageal reflux symptoms plus additional risk factors should be considered for screening. Mucosal change consistent with Barrett esophagus is visualized during upper endoscopy; biopsy confirms the diagnosis and determines if dysplasia is present. Management of Barrett esophagus depends on the presence and severity of dysplasia; endoscopic treatment of dysplasia decreases the risk of malignant transformation. Surveillance after diagnosis is recommended to monitor for dysplasia and diagnose and treat esophageal adenocarcinoma at an earlier stage. Patients with Barrett esophagus should be offered proton pump inhibitor therapy to control reflux symptoms and possibly decrease the risk of developing esophageal adenocarcinoma. Statins, nonsteroidal anti-inflammatory drugs, and aspirin are associated with a decreased risk of esophageal adenocarcinoma in patients with Barrett esophagus; however, they should not generally be prescribed in the absence of another indication. Mortality benefits of screening and surveillance are uncertain.

Laparoscopic total fundoplication is superior to medical treatment for reducing the cancer risk in Barrett's esophagus: a long-term analysis.

The present study aims to compare the effectiveness of surgical and medical therapy in reducing the risk of cancer in Barrett's esophagus in a long-term evaluation. A prospective cohort was designed that compared Barrett's esophagus patients submitted to medical treatment with omeprazole or laparoscopic Nissen fundoplication. The groups were compared using propensity score matching paired by Barrett's esophagus length. A total of 398 patients met inclusion criteria. There were 207 patients in the omeprazole group (Group A) and 191 in the total fundoplication group (Group B). After applying the propensity score matching paired by Barrett's esophagus length, the groups were 180 (Group A) and 190 (Group B). Median follow-up was 80 months. Group B was significantly superior for controlling GERD symptoms. Group B was more efficient than Group A in promoting Barrett's esophagus regression or blocking its progression. Group B was more efficient than Group A in preventing the development of dysplasia and cancer. Logistic regression was performed for the outcomes of adenocarcinoma and dysplasia. Age and body mass index were used as covariates in the logistic regression models. Even after regression analysis, Group B was still superior to Group A to prevent esophageal adenocarcinoma or dysplasia transformation (odds ratio [OR]: 0.51; 95% confidence interval [CI]: 0.27-0.97, for adenocarcinoma or any dysplasia; and OR: 0.26; 95% CI: 0.08-0.81, for adenocarcinoma or high-grade dysplasia). Surgical treatment is superior to medical management, allowing for better symptom control, less need for reflux medication use, higher regression rate of the columnar epithelium and intestinal metaplasia, and lower risk for progression to dysplasia and cancer.

Epidemiology and prevention of oesophageal adenocarcinoma.

Oesophageal adenocarcinoma (OAC) develops from columnar metaplasia of the distal oesophagus, Barrett's oesophagus (BO), secondary to chronic gastro-oesophageal reflux disease (GORD). In the present review, the stepwise development of GORD, BO and OAC is presented and the evidence of OAC prevention, including treatment with proton pump inhibitors (PPIs). PPIs are the main treatment of GORD and BO, with some evidence of prevention of OAC in these patients. However, as about 40% of OAC patient do not report a history of GORD and fewer than 15% of OAC cases are detected in individuals during BO surveillance, prevention of OAC is limited by PPI use in GORD and BO patients.

Preventing Uterine Cervix Cancer: The Clinical Meaning of Atypical Glandular Cells.

OBJECTIVE: To determine the prevalence of the atypical glandular cells (AGCs) cytology and to analyze its clinical significance in different age ranges. METHODS: Retrospective observational study using computerized data from the Brazilian National Cancer Institute, including women screened between January 2002 and December 2008. The women included were those with an AGC result who were properly followed-up with colposcopy and a second cytology. RESULTS: A total of 132,147 cytopathological exams were performed during the study period. Five-hundred and thirty-three (0.4%) women with AGC cytology were identified and, of these, 69.41% (370/533) were properly referred for colposcopy and a new cytology. Most of the women (79.2%) with a 1st or 2nd AGC cytology were between the ages of 25 and 54 years. The 2nd cytology demonstrated 67.6% (250/370) of normality, 24.5% (91/370) of squamous atypia, and 6.2% (23/370) of AGC, 0.8% (3/370) adenocarcinoma in situ and 0.8% (3/370) adenocarcinoma invasor. On biopsy of the women with a second AGC cytology, 43.4% (10/23) had normal histology, 43.4% (10/23) had squamous lesions, 8.7% (2/23) had invasive adenocarcinoma, and 1.2% (1/23) had an inconclusive report. All of the women with high-grade squamous intraepithelial lesion (HSIL) or invasive adenocarcinoma (respectively 5 and 2 patients), after a 2nd AGC cytology were 25 years old or older. CONCLUSION: The prevalence of the AGC cytology was low in the studied population. Most of the AGC cytology cases occurred in adult women between the ages of 25 and 54. Although most of the patients had normal histology after follow-up, several of them presented with squamous intraepithelial lesions or invasive adenocarcinoma.

OBJETIVO: Determinar a prevalência de citologia com laudo de células glandulares atípicas (AGCs, na sigla em inglês) e analisar a significância clínica nas diferentes faixas etárias MéTODOS: Estudo observacional retrospectivo, usando os dados arquivados no sistema do Instituto Nacional de Câncer no Brasil, que incluiu mulheres rastreadas entre janeiro de 2002 a dezembro de 2008. As mulheres incluídas tinham citologia com resultado de AGCs, que foram acompanhadas com colposcopia e nova citologia RESULTADOS: Um total de132,147 exames citopatológicos foram incluídos durante o período de estudo. Quinhentas e trinta e três mulheres com citologia de AGC foram identificadas e destas, 69.41% (370) foram encaminhadas para colposcopia e nova citologia. A prevalência de citologia de AGC na população estudada foi 0.4%. A maioria das mulheres (79.22%) com resultado citológico de AGC tinham idade entre 25 e 54 anos. A segunda citologia demonstrou 67.56% (250/370) de normalidade, 24.5% (91/370) de atipias escamosas, e 6.2% (23/370) de AGC. Na biopsia das mulheres com a 2ª citologia de AGC, 43.4% (10/23) tinham histologia normal, 43.4% (10/23) tinha lesões escamosas, 8.7% (2/23) tinha adenocarcinoma invasor e 1.2% (1/23) tinha laudo inconclusivo. Todas as mulheres com lesões intraepiteliais escamosas de alto grau (HSIL, na sigla em inglês) ou adenocarcinoma invasor (respectivamente 5 e 2 pacientes), após a 2ª citologia com AGC, tinham 25 anos de idade ou mais. CONCLUSãO: A prevalência de citologia com AGC foi baixa na população estudada. Muitos casos de citologia com AGC apareceram em mulheres adultas, entre 25 e 54 anos de idade. Embora a maioria das pacientes tiveram histologia normal após seguimento, várias apresentaram lesões intraepiteliais escamosas ou glandulares invasoras.

Association Between Aspirin Use and Gastric Adenocarcinoma: A Prospective Cohort Study.

Prospective data examining the association of aspirin use, according to dose and duration, with long-term risk of gastric adenocarcinoma in non-Asian cohorts are lacking. We evaluated the association between aspirin use and risk of gastric adenocarcinoma in two large prospective U.S. cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study. Cox proportional hazards regression models were used to calculate multivariable adjusted HRs and 95% confidence intervals (CI). Among the 159,116 participants, we documented 316 gastric adenocarcinoma cases (176 women, 140 men) over 34 years encompassing 4.5 million person-years. Among women, regular aspirin use (at least two times or more per week) was significantly associated with lower risk of gastric adenocarcinoma (multivariable HR, 0.52; 95% CI, 0.37-0.73) compared with nonregular use. However, regular aspirin use was not associated with gastric adenocarcinoma risk among men (multivariable HR, 1.08; 95% CI, 0.77-1.52; Pheterogeneity for sex = 0.003). Among women, the lower risk of gastric adenocarcinoma was more apparent with increasing duration of aspirin use (Ptrend < 0.001) and more than five tablets per week (multivariable HR, 0.51; 95% CI, 0.31-0.84). Regular, long-term aspirin use was associated with lower risk of gastric adenocarcinoma among women, but not men. The benefit appeared after at least 10 years of use and was maximized at higher doses among women. The heterogeneity by sex in the association of aspirin use with risk of gastric adenocarcinoma requires further investigation. PREVENTION RELEVANCE: Novel prevention is urgently needed to reduce incidence and mortality of gastric cancer. We found that regular aspirin use was associated with lower risk of gastric adenocarcinoma among women, but not men. The benefit appeared after at least 10 years of use and was maximized at higher doses among women. See related Spotlight, p. 213.

Proton pump inhibitors may reduce the risk of high-grade dysplasia and/or esophageal adenocarcinoma in Barrett's esophagus: a systematic review and meta-analysis.

BACKGROUND: Barrett's esophagus (BE) is an important risk factor for high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). The effect of proton pump inhibitors (PPIs) on the chemoprevention of HGD and/or EAC arising from BE remains controversial. RESEARCH DESIGN AND METHODS: PubMed, EMBASE, and Cochrane Library databases were systematically searched. Risk ratios (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled by a random-effect model. Heterogeneity and its potential source were assessed. RESULTS: Fifteen studies with 26,291 BE patients were included. Meta-analysis of eight cohort studies showed that PPIs can significantly reduce the risk of HGD and/or EAC in BE patients (RR = 0.46; P < 0.001), but meta-analysis of six case-control studies showed no significant benefit of PPIs (OR = 0.64; P = 0.334). Heterogeneity was significant among both cohort and case-control studies, which might be attributed to the information sources of PPIs. There was no significant protective effect of high-dose PPIs on HGD and/or EAC in one RCT (RR = 0.84; P = 0.21), meta-analysis of two cohort studies (RR = 0.61; P = 0.28), or meta-analysis of two case-control studies (OR = 0.32; P = 0.08). CONCLUSIONS: Chemoprevention of HGD and/or EAC by PPIs may be considered in BE patients. However, there might not be further preventive effect of high-dose PPIs.

Inhibition of the BMP pathway prevents development of Barrett's-associated adenocarcinoma in a surgical rat model.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). AIM: To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. METHODS: After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. RESULTS: Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. CONCLUSION: In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome.

Chemoprevention of Oesophageal Squamous-Cell Carcinoma and Adenocarcinoma: A Multicentre Retrospective Cohort Study.

BACKGROUND: Oesophageal cancer comprises 2 different histological variants: oesophageal squamous-cell carcinoma (ESCC) and adenocarcinoma (EAC). While there are multiple therapeutic options for both types, patients with advanced or metastatic oesophageal cancer still suffer from poor prognosis. AIMS: The study aimed to examine the association between the risk of oesophageal cancer and medications and to estimate the chemopreventive effects of commonly used drugs. METHODS: A multicentre retrospective cohort study was conducted using data from 9 hospital databases of hospitalized patients between 2014 and 2019. The primary outcomes were ESCC and EAC. The association of oesophageal cancer with drug use and clinical factors was evaluated. Odds ratios (ORs) were adjusted for age, sex, Charlson comorbidity index scores, and smoking with/without gastro-oesophageal reflux disease. RESULTS: The use of proton pump inhibitors (PPIs) (adjusted OR [aOR] 0.48, p < 0.0001), aspirin (aOR 0.32, p < 0.0001), cyclooxygenase-2 inhibitor (COX2I) (aOR 0.70, p = 0.0005), steroid (aOR 0.19, p < 0.0001), statin (aOR 0.43, p < 0.0001), and metformin (aOR 0.42, p < 0.0001) was associated with a lower risk of ESCC than that in non-use. The use of aspirin (aOR 0.33, p = 0.0006) and steroids (aOR 0.54, p = 0.022) was associated with a lower risk of EAC than that in non-use. CONCLUSION: COX2Is, statins, metformin, and PPIs could help in prevention of ESCC, and aspirin and steroids may be chemopreventive for both types of oesophageal cancer.

Implantation of a neoantigen-targeted hydrogel vaccine prevents recurrence of pancreatic adenocarcinoma after incomplete resection.

Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVaxTM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.

Lifestyle, WCRF/AICR Recommendations, and Esophageal Adenocarcinoma Risk: A Systematic Review of the Literature.

One of the most notable changes in the epidemiology of esophageal cancer (EC) is the rising incidence and prevalence of esophageal adenocarcinoma (EAC) in developed countries. The aim of this systematic review was to collect and summarize all the available evidence regarding lifestyle, diet, and EAC risk. We searched the PubMed and Scopus databases in January 2021 for studies providing information about lifestyle, diet, WCRF/AICR recommendations, and EAC risk; published in English; without a time filter. The Newcastle-Ottawa Scale was used to assess risk of bias. The results are stratified by risk factor. A total of 106 publications were included. Half of the case-control studies were judged as high quality, whilst practically all cohort studies were judged as high quality. Body mass index and waist circumference were associated with increased EAC risk. Physical activity did not appear to have a significant direct role in EAC risk. A diet rich in fruit, vegetables, and whole grains appeared to be more protective than a Western diet. Alcohol does not seem to be related to EAC, whereas smokers, particularly heavy smokers, have an increased risk of EAC. Prevention remains the best option to avert EAC. Comprehensible and easy to follow recommendations should be provided to all subjects. Protocol ID number: CRD-42021228762, no funds received.

Insulin/IGF-1 Signaling Is Downregulated in Barrett's Esophagus Patients Undergoing a Moderate Calorie and Protein Restriction Program: A Randomized 2-Year Trial.

Obesity and associated insulin resistance (Ins-R) have been identified as important risk factors for esophageal adenocarcinoma development. Elevated calories and protein consumption are also associated with Ins-R and glucose intolerance. We investigated the effect of a 24-month moderate calorie and protein restriction program on overweight or obese patients affected by Barrett's esophagus (BE), as no similar dietary approach has been attempted to date in this disease context. Anthropometric parameters, levels of serum analytes related to obesity and Ins-R, and the esophageal insulin/IGF-1 signaling pathway were analyzed. This study is registered with ClinicalTrials.gov, number NCT03813381. Insulin, C-peptide, IGF-1, IGF-binding protein 3 (IGFBP3), adipokines, and esophageal expression of the main proteins involved in insulin/IGF-1 signal transduction were quantified using Luminex-XMAP® technology in 46 patients who followed the restriction program (IA) and in 54 controls (CA). Body mass index and waist circumference significantly decreased in 76.1% of IA and 35.2% of CA. IGF-1 levels were reduced in 71.7% of IA and 51.8% of CA. The simultaneous reduction of glycaemia, IGF-1, the IGF-1/IGFBP3 ratio, and the improvement in weight loss-dependent insulin sensitivity, were associated with the downregulation of the insulin/IGF-1 signal on BE tissue. The proposed intervention program was an effective approach to counteract obesity-associated cancer risk factors. The improvement in metabolic condition resulted in a downregulation of the ERK-mediated mitogenic signal in 43.5% of patients, probably affecting the molecular mechanism driving adenocarcinoma development in BE lesions.