Role of endoscopic therapy in early esophageal cancer

Esophageal carcinoma is a highly lethal cancer associated with high morbidity and mortality. Esophageal squamous cell carcinoma and esophageal adenocarcinoma are the two distinct histological types. There has been significant progress in endoscopic diagnosis and treatment of early stages of cancer using resection and ablation techniques, as shown in several trials in the recent past. Earlier detection of esophageal cancer and advances in treatment modalities have lead to improvement in the 5-year survival from 5% to about 20% in the past decade. Endoscopic eradication therapy is the preferred modality of treatment in cancer limited to mucosal layer of the esophagus as there is very low risk of lymph node metastasis, leading to high cure rates, low risk of recurrence and with few adverse effects. The most common adverse events seen are strictures, bleeding and rarely perforation which can be endoscopically managed. In patients with recurrent advanced disease or invasive tumor, esophagectomy with lymph node dissection remains the mainstay of treatment. There is debate on post-endoscopic surveillance with some studies suggesting closer follow up with upper endoscopy every 6 mo for the first 1-2 years and then annually for the 3 years while others recommending the appropriate action only if symptoms or other abnormalities develop. Overall, the field of endoscopic therapy is still evolving and focus should be placed on careful patient selection using a multidisciplinary approach.

Efficacy of peroral endoscopic myotomy vs other achalasia treatments in improving esophageal function

AIM: To assess and compare the esophageal function after peroral endoscopic myotomy(POEM) vs other conventional treatments in achalasia.METHODS: Chart review of all achalasia patients who underwent POEM, laparoscopic Heller myotomy(LHM) or pneumatic dilation(PD) at our institution between January 2012 and March 2015 was performed. Patient demographics, type of achalasia, prior treatments, pre- and post-treatment timed barium swallow(TBE) and high-resolution esophageal manometry(HREM) findings were compared between the three treatment groups. Patients who had both pre- and 2 mo posttreatment TBE or HREM were included in the final analysis. TBE parameters compared were barium column height, width and volume of barium remaining at 1 and 5 min. HREM parameters compared were basal lower esophageal sphincter(LES) pressures and LES-integrated relaxation pressures(IRP). Data are presented as mean ± SD, median [25th, 75 th percentiles] or frequency(percent). Analysis of variance, KruskalWallis test, Pearsons χ~2 test and Fishers Exact tests were used for analysis.RESULTS: A total of 200 achalasia patients were included of which 36 underwent POEM, 22 underwent PD and 142 underwent LHM. POEM patients were older(55.4 ± 16.8 years vs 46.5 ± 15.7 years, P = 0.013) and had higher BMI than LHM(29.1 ± 5.9 kg/m^2 vs 26 ± 5.1 kg/m^2, P = 0.012). More number of patients in POEM and PD groups had undergone prior treatments compared to LHM group(72.2% vs 68.2% vs 44.3% respectively, P = 0.003). At 2 mo post-treatment, all TBE parameters including barium column height, width and volume remaining at 1 and 5 min improved significantly in all three treatment groups(P = 0.01 to P < 0.001) except the column height at 1 min in PD group(P = 0.11). At 2 mo post-treatment, there was significant improvement in basal LES pressure and LES-IRP in both LHM(40.5 mm Hg vs 14.5 mm Hg and 24 mm Hg vs 7.1 mm Hg respectively, P < 0.001) and POEM groups(38.7 mm Hg vs 11.4 mm Hg and 23.6 mm Hg vs 6.6 mm Hg respectively, P < 0.001). However, when the efficacy of three treatments were compared to each other in terms of improvement in TBE or HREM parameters at 2 mo, there was no significant difference(P > 0.05).CONCLUSION: POEM, PD and LHM were all effective in improving esophageal function in achalasia at shortterm. There was no difference in efficacy between the three treatments.

Vitamin D in esophageal cancer: Is there a role for chemoprevention?

Vitamin D has emerged as a promising anti-cancer agent due to its diverse biological effects on tumor differentiation, apoptosis and suppression of cellular proliferation. Current evidence suggests a protective role of vitamin D in colon cancer. The effect of vitamin D on esophageal cancer remains controversial. Multiple studies investigated the association between vitamin D and esophageal cancer, employing different modes of assessment of vitamin D status such as serum 25-hydroxyvitamin D levels, vitamin D dietary intake or exposure to ultraviolet B(UVB) radiation. Genetic variations of the vitamin D receptor(VDR) gene and VDR expression in esophageal specimens have also been investigated. Ecological studies evaluating exposure to UVB radiation yielded an inverse correlation with esophageal cancer. When vitamin D dietary intake was assessed, direct association with esophageal cancer was observed. However, circulating 25-hydroxyvitamin D concentrations showed inconsistent results. In this review article, we present a detailed summary of the current data on the effects of vitamin D on various histological subtypes of esophageal cancer and their precursor lesions. Well-powered prospective studies with accurate measurement of vitamin D status are needed before chemoprevention with vitamin D is recommended, as current evidence does not support a chemopreventive role of vitamin D against esophageal cancer. Future studies looking at the incidence of esophageal cancer in patients with pre-cancerous lesions(Barrett's esophagus and squamous cell dysplasia) receiving vitamin D supplementation are needed.

Cryotherapy in the management of premalignant and malignant conditions of the esophagus

Endoscopic cryotherapy is a relatively new thermal ablative modality used for the treatment of neoplastic lesions of the esophagus. It relies on cycles of rapid cooling and thawing to induce tissue destruction with a cryogen(liquid nitrogen or carbon dioxide) leading to intra and extra-cellular damage. Surgical treatment was once considered the standard therapeutic intervention for neoplastic diseases of the esophagus and is associated with considerable rates of morbidity and mortality. Several trials that evaluated cryotherapy in Barrett's esophagus(BE) associated neoplasia showed reasonable efficacy rates and safety profile. Cryotherapy has also found applications in the treatment of esophageal cancer, both for curative and palliative intent. Cryotherapy has also shown promising results as salvage therapy in cases refractory to radiofrequency ablation treatment. Cryoballoon focal ablation using liquid nitrogen is a novel mode of cryogen delivery which has been used for the treatment of BE with dysplasia and squamous cell carcinoma. Most common side effects of cryotherapy reported in the literature include mild chest discomfort, esophageal strictures and bleeding. In conclusion, cryotherapy is an effective and safe method for the treatment of esophageal neoplastic processes, ranging from early stages of low grade dysplasia to esophageal cancer.

Resection of early esophageal neoplasms: The pendulum swings from surgical to endoscopic management

Esophageal cancer is a highly lethal disease and is the sixth leading cause of cancer related mortality in the world.The standard treatment is esophagectomy which is associated with significant morbidity and mortality.This led to development of minimally invasive,organ sparing endoscopic therapies which have comparable outcomes to esophagectomy in early cancer.These include endoscopic mucosal resection and endoscopic submucosal dissection.In early squamous cell cancer,endoscopic submucosal dissection is preferred as it is associated with cause specific 5-year survival rates of 100%for M1 and M2 tumors and 85%for M3 and SM1 tumors and low recurrence rates.In early adenocarcinoma,endoscopic resection of visible abnormalities is followed by ablation of the remaining flat Barrett’s mucosa to prevent recurrences.Radiofrequency ablation is the most widely used ablation modality with others being cryotherapy and argon plasma coagulation.Focal endoscopic mucosal resection followed by radiofrequency ablation leads to eradication of neoplasia in 93.4%of patients and eradication of intestinal metaplasia in 73.1%of patients.Innovative techniques such as submucosal tunneling with endoscopic resection are developed for management of submucosal tumors of the esophagus.This review includes a discussion of various endoscopic techniques and their clinical outcomes in early squamous cell cancer,adenocarcinoma and submucosal tumors.An overview of comparison between esophagectomy and endoscopic therapy are also presented.

Healthcare utilization and costs associated with gastroparesis

To use a national database of United States hospitals to evaluate the incidence and costs of hospital admissions associated with gastroparesis. METHODSWe analyzed the National Inpatient Sample Database (NIS) for all patients in whom gastroparesis (ICD-9 code: 536.3) was the principal discharge diagnosis during the period, 1997-2013. The NIS is the largest publicly available all-payer inpatient care database in the United States. It contains data from approximately eight million hospital stays each year. The statistical significance of the difference in the number of hospital discharges, length of stay and hospital costs over the study period was determined by regression analysis. RESULTSIn 1997, there were 3978 admissions with a principal discharge diagnosis of gastroparesis as compared to 16460 in 2013 (P < 0.01). The mean length of stay for gastroparesis decreased by 20 % between 1997 and 2013 from 6.4 d to 5.1 d (P < 0.001). However, during this period the mean hospital charges increased significantly by 159 % from $13350 (after inflation adjustment) per patient in 1997 to $34585 per patient in 2013 (P < 0.001). The aggregate charges (i.e., “national bill”) for gastroparesis increased exponentially by 1026 % from $50456642 ± 4662620 in 1997 to $568417666 ± 22374060 in 2013 (P < 0.001). The percentage of national bill for gastroparesis discharges (national bill for gastroparesis/total national bill) has also increased over the last 16 years (0.0013% in 1997 vs 0.004% in 2013). During the study period, women had a higher frequency of gastroparesis discharges when compared to men (1.39/10000 vs 0.9/10000 in 1997 and 5.8/10000 vs 3/10000 in 2013). There was a 6-fold increase in the discharge diagnosis of gastroparesis amongst type 1 DM and 3.7-fold increase amongst type 2 DM patients over the study period (P < 0.001). CONCLUSIONThe number of inpatient admissions for gastroparesis and associated costs have increased significantly over the last 16 years. Inpatient costs associated with gastroparesis contribute significantly to the national healthcare bill. Further research on cost-effective evaluation and management of gastroparesis is required.

Lymphocytic esophagitis: Still an enigma a decade later

Lymphocytic esophagitis (LE) is a clinicopathologic entity first described by Rubio et al in 2006. It is defined as peripapillary intraepithelial lymphocytosis with spongiosis and few or no granulocytes on esophageal biopsy. This definition is not widely accepted and the number of lymphocytes needed to make the diagnosis varied in different studies. Multiple studies have described potential clinical associations and risk factors for LE, such as old age, female gender and smoking history. This entity was reported in inflammatory bowel disease in the pediatric population but not in adults. Other associations include gastroesophageal reflux disease and primary esophageal motility disorders. The most common symptom is dysphagia, with a normal appearing esophagus on endoscopy, though esophageal rings, webs, nodularities, furrows and strictures have been described. Multiple treatment modalities have been used such as proton pump inhibitors and topical steroids. Esophageal dilation seems to be therapeutic when dysphagia is present along with esophageal narrowing secondary to webs, rings or strictures. The natural history of the disease remains unclear and needs to be better delineated. Overall, lymphocytic esophagitis seems to have a chronic and benign course, except for two cases of esophageal perforation in the literature, thought to be secondary to this entity.

Recent advances in third space or intramural endoscopy

Third space endoscopy or intramural endoscopy is based on the principle that the deeper layers of the gastrointestinal tract can be accessed by tunneling in the submucosal space and maintaining the integrity of the overlying mucosa.The era of third space endoscopy started with peroral endoscopic myotomy(POEM)for treatment of achalasia and has expanded to treat various other gastrointestinal disorders.The technique is also currently used for treatment of refractory gastroparesis,Zenker’s diverticulum(ZD),resection of subepithelial tumors and early cancers of the gastrointestinal tract and Hirschsprung’s disease(HD).These procedures are rapidly emerging as minimally invasive alternatives to conventional surgery.They are safe and effective with excellent outcomes.This review focuses on the evolution and current applications of third space endoscopy in various gastrointestinal disorders.Key points:(1)Third space or intramural endoscopy initially started with the POEM procedure for treatment of achalasia;(2)Advancements in procedural techniques have expanded its application to treat other gastrointestinal disorders such as refractory gastroparesis,ZD,HD,resection of subepithelial tumors and early gastrointestinal cancers;(3)These procedures are highly effective with excellent outcomes and low complication rates;and(4)Third space endoscopic procedures are rapidly emerging as minimally invasive alternatives to conventional surgery.

Endoscopic therapy for Barrett's esophagus and early esophageal cancer:Where do we go from here?

Since Barrett's esophagus is a precancerous condition,efforts have been made for its eradication by various ablative techniques.Initially,laser ablation was attempted in non-dysplastic Barrett's esophagus and subsequently,endoscopic ablation using photodynamic therapy was used in Barrett's patients with high-grade dysplasia who were poor surgical candidates.Since then,various ablative therapies have been developed with radiofrequency ablation having the best quality of evidence.Resection of dysplastic areas only without complete removal of entire Barrett's segment is associated with high risk of developing metachronous neoplasia.Hence,the current standard of management for Barrett's esophagus includes endoscopic mucosal resection of visible abnormalities followed by ablation to eradicate remaining Barrett's epithelium.Although endoscopic therapy cannot address regional lymph node metastases,such nodal involvement is present in only 1% to 2% of patients with intramucosal adenocarcinoma in Barrett esophagus and therefore is useful in intramucosal cancers.Post ablation surveillance is recommended as recurrence of intestinal metaplasia and dysplasia have been reported.This review includes a discussion of the technique,efficacy and complication rate of currently available ablation techniques such as radiofrequency ablation,cryotherapy,argon plasma coagulation and photodynamic therapy as well as endoscopic mucosal resection.A brief discussion of the emerging technique,endoscopic submucosal dissection is also included.

Risk of progression of Barrett's esophagus in patients with cirrhosis

To study Barrett’s esophagus (BE) in cirrhosis and assess progression to esophageal adenocarcinoma (EAC) compared to non-cirrhotic BE controls.METHODSCirrhotic patients who were found to have endoscopic evidence of BE confirmed by the presence of intestinal metaplasia on histology from 1/1/2000 to 12/1/2015 at Cleveland Clinic were included. Cirrhotic patients were matched 1:4 to BE controls without cirrhosis. Age, gender, race, BE length, hiatal hernia size, Child-Pugh (CP) class and histological findings were recorded. Cases and controls without high-grade dysplasia (HGD)/EAC and who had follow-up endoscopies were studied for incidence of dysplasia/EAC and to assess progression rates. Univariable conditional logistic regression was done to assess differences in baseline characteristics between the two groups.RESULTSA total of 57 patients with cirrhosis and BE were matched with 228 controls (BE without cirrhosis). The prevalence of dysplasia in cirrhosis and controls were similar with 8.8% vs 12% with low grade dysplasia (LGD) and 12.3 % vs 19.7% with HGD or EAC (P = 0.1). In the incidence cohort of 44 patients with median follow-up time of 2.7 years [interquartile range 1.0, 4.8], there were 7 cases of LGD, 2 cases of HGD, and 2 cases of EAC. There were no differences in incidence rates of HGD/EAC in nondysplastic BE between cirrhotic cases and noncirrhotic controls (1.4 vs 1.1 per 100 person- years, P = 0.8). In LGD, cirrhotic patients were found to have higher rates of progression to HGD/EAC compared to control group though this did not reach statistical significance (13.7 vs 8.1 per 100 person- years, P = 0.51). A significant association was found between a higher CP class and neoplastic progression of BE in cirrhotic patients (HR =7.9, 95%CI: 2.0-30.9, P = 0.003).CONCLUSIONCirrhotics with worsening liver function are at increased risk of progression of BE. More frequent endoscopic surveillance might be warranted in such patients.

Clinical significance and management of Barrett's esophagus with epithelial changes indefinite for dysplasia

Barrett's esophagus(BE) is defined as the extension of salmon-colored mucosa into the tubular esophagus ≥1 cm proximal to the gastroesophageal junction with biopsy confirmation of intestinal metaplasia. Patients with BE are at increased risk of esophageal adenocarcinoma(EAC), and undergo endoscopic surveillance biopsies to detect dysplasia or early EAC. Dysplasia in BE is classified as no dysplasia, indefinite for dysplasia(IND), low grade dysplasia(LGD) or high grade dysplasia(HGD). Biopsies are diagnosed as IND when the epithelial abnor-malities are not sufficient to diagnose dysplasia or the nature of the epithelial abnormalities is uncertain due to inflammation or technical issues. Specific diagnostic criteria for IND are not well established and its clinical significance and management has not been well studied. Previous studies have focused on HGD in BE and led to changes and improvement in the management of BE with HGD and early EAC. Only recently, IND and LGD in BE have become focus of intense study. This review summarizes the definition, neoplastic risk and clinical management of BE IND.

Expression of p53 predicts risk of prevalent and incident advanced neoplasia in patients with Barrett’s esophagus and epithelial changes indefinite for dysplasia

Background and aims:Patients with Barrett’s esophagus(BE)are at an increased risk for developing esophageal adenocarcinoma(EAC);thus they may undergo regular endoscopic surveillance.If epithelial changes cannot be unequivocally classified as negative or positive for dysplasia,a diagnosis of indefinite for dysplasia(IND)is recommended.Several biomarkers have been proposed as markers or predictors of neoplasia in the general BE population;however,their significance is not clear in patients with BE-IND.We therefore performed a retrospective study to determine whether expression of these biomarkers was associated with the development of neoplasia in BE-IND patients.Methods:We searched our archives to identify all cases of BE-IND diagnosed between January 1992 and December 2007.Immunohistochemical analyses were used to semi-quantify the expression of p53,a-methylacyl-CoA racemase(AMACR),and cyclin D1.A univariate analysis was used to identify predictors for prevalent and incident neoplasia and advanced neoplasia.Results:Among the 103 patients with an index diagnosis of BE-IND who were included in this study,81(78.6%)underwent a follow-up biopsy within 12 months of diagnosis;10(12.3%)had neoplasia,including four(4.9%)with advanced neoplasia.Among 79 patients without prevalent neoplasia who underwent more than 1 year of follow-up,18(22.8%)had developed neoplasia,including four(5.1%)with advanced neoplasia.AMACR and cyclin D1 expression levels were not correlated with prevalent or incident neoplasia;however,high p53 expression(>5%)was associated with prevalent advanced neoplasia on surveillance biopsy(P=0.04)and with an increased risk of progression to advanced neoplasia(HR=12;P=0.03).Conclusion:In this study,p53 expression was found to be predictive of prevalent advanced neoplasia and progression to advanced neoplasia in patients with BE-IND.