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REVIEW ARTICLE

Approach to the Post-Ablation Barrett's Esophagus Patient

Kahn, Allon MD1; Shaheen, Nicholas J. MD, MPH2; Iyer, Prasad G. MD, MSc3

Author Information
The American Journal of Gastroenterology: June 2020 - Volume 115 - Issue 6 - p 823-831
doi: 10.14309/ajg.0000000000000514
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Abstract

INTRODUCTION

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC) (1), a lethal cancer with exponentially rising incidence (2–4). Progression to EAC is thought to occur by the development of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) (5–7), although patients rarely display all these intermediate stages clinically. The principal determinant of poor survival in EAC is the high rate of locally advanced disease at clinical presentation (8). Thus, endoscopic treatment of dysplasia and EAC arising in BE provides an opportunity for the prevention and early treatment of EAC (9).

Endoscopic eradication therapy (EET) is the standard management strategy for BE with dysplasia (LGD or HGD) and intramucosal (T1a) EAC (10). This approach has outcomes comparable with those of esophagectomy (11,12) and is cost effective (13,14). EET consists of endoscopic resection (cap-assisted endoscopic mucosal resection and/or endoscopic submucosal dissection) of all visible lesions, followed by ablation of the remaining Barrett's epithelium (15). Radiofrequency ablation (RFA) remains the first-line ablation modality because of randomized clinical trials supporting its efficacy (10). The safety of RFA is also well established with a large meta-analysis indicating an overall adverse event rate of 8.8% (5.6% strictures, 1% bleeding, and 0.6% perforation) (16). Other ablation modalities such as cryotherapy have promising initial evidence (17). The endpoint of EET is complete eradication of dysplasia (CE-D) and intestinal metaplasia (CE-IM), which are achieved in approximately 90% and 80% of the patients, respectively (18).

Several factors suggest that an increasing population of patients will undergo EET in the western societies. The incidence of clinically diagnosed BE appears to be rising, even adjusting for increases in the total number of endoscopic procedures (19–21). In addition, epidemiological studies suggest increases in the prevalence of GERD and obesity, which are the risk factors for BE and EAC (22,23). Endoscopic optical enhancements, such as high-definition monitors and integrated virtual chromoendoscopy, are now a commonplace and have been shown to enhance dysplasia detection in BE (24,25). The availability of safe and effective ablation technology has further facilitated this trend (26).

Given the extensive body of evidence for EET in BE, guidelines are specific and evidence based. However, the body of evidence on the management of patients with BE after EET is still limited, and most guidelines remain expert opinion based. This review discusses the principles of managing patients with BE after successful EET (defined as those with no endoscopic or histologic evidence of intestinal metaplasia [IM]) with specific focus on endoscopic surveillance, reflux management, and recurrence.

ENDOSCOPIC SURVEILLANCE AFTER SUCCESSFUL EET

Achieving CE-IM is the optimal endpoint for EET and often requires multiple endoscopic procedures over several months. However, the endoscopic follow-up extends beyond the treatment period after which patients who achieve CE-IM are enrolled in a program of endoscopic surveillance. The rationale for surveillance is to detect recurrence of BE and dysplasia, offering an opportunity for further endoscopic intervention to prevent EAC.

Defining eradication

A clear definition of successful EET (CE-IM) is imperative before discussing recurrence. The definition of CE-IM varies considerably in the existing literature on the basis of both number of endoscopic biopsy sessions and biopsy protocols used. These variations are principally ascribed with the intent to limit sampling errors. Studies have defined CE-IM as either 1 (27–30) or 2 (31–33) endoscopic biopsy sessions demonstrating no IM on surveillance histology after the BE segment is visibly eradicated. Sensitivity analyses of the US RFA Registry and Ablation of Intestinal Metaplasia and Dysplasia Trial data demonstrated no significant change in rate of recurrence with CE-IM defined as 1 or 2 endoscopic biopsy sessions (34,35). However, a recent meta-analysis showed that studies defining CE-IM as a single negative endoscopy were associated with a higher rate of recurrent IM in the first year of surveillance, whereas those using a 2-endoscopy CE-IM definition did not reveal this association (36). This was attributed to the potential sampling error in studies using a single negative histology as a definition of CE-IM.

Furthermore, although some studies specified 4-quadrant biopsies of the gastroesophageal junction (GEJ) and gastric cardia (30,31,37–39) after ablation to define CE-IM, others only specified biopsies within the tubular esophagus (29,40,41). This is relevant for several important reasons. Ablation protocols have evolved to specify ablation of the GEJ in addition to treating BE in the tubular esophagus to potentially reduce the risk of recurrence after successful ablation (42,43). This parallels observations of recurrent IM and dysplasia in the gastric cardia after RFA (28,44) and a growing body of research suggesting that BE may arise from progenitor cells in the gastric cardia (45,46).

Hence, although the optimal definition of CE-IM after EET remains to be conclusively defined, the use of 2 negative surveillance endoscopies (with biopsies from the tubular esophagus and the GEJ) is likely to reduce the sampling error. Furthermore, the definition of CE-IM should include eradication of gastric cardia IM, when present, during EET. Finally, complete remission of IM (CRIM) is synonymous with CE-IM and may be used interchangeably.

Recurrence rates after EET

Recurrence is defined by the presence of IM, dysplasia, or EAC in the tubular esophagus or GEJ in patients undergoing endoscopic surveillance after successful EET, as defined by CE-IM. Recurrence can be classified as visible if endoscopically detectable or as nonvisible if only detected by surveillance protocol biopsies of the normal-appearing neosquamous epithelium and/or the GEJ. Recurrence rates from 2 systematic reviews and meta-analyses (47,48) are displayed in Table 1 along with rates from more recent cohort studies (33,49). These studies demonstrate an annual incidence of 8%–10% for IM recurrence and 2%–3% for dysplasia recurrence per patient-year of surveillance. Importantly, although recurrence is reported more frequently in the first year after CE-IM, this may be a consequence of inadequately treated prevalent disease with sampling error, leading to a premature definition of CE-IM (36).

Table 1.
Table 1.:
Recurrence rates after radiofrequency ablation in selected studies

Histology of recurrence

Most recurrences after EET are nondysplastic (35). However, although progression to EAC in BE tends to follow an orderly pathway from IM through increasing grades of dysplasia, recurrence after EET may present as dysplasia or EAC. Existing studies indicate that pretreatment histology may enhance the likelihood of this phenomenon. In a meta-analysis of 7 RFA studies with an entry histology of dysplastic BE or intramucosal adenocarcinoma (IMCa), dysplasia recurred at an annual incidence of 6% per patient-year, which is higher than the recurrence rates in an unselected BE population undergoing EET (48). Most dysplastic recurrences tend to occur at or below the grade of the baseline histology (31,50). In a study of 1,634 patients who underwent CE-IM, only 6% of the patients with recurrence after EET demonstrated a grade of histology, which was higher than the pretreatment histology (35).

Location of recurrence

The anatomical distribution of recurrence also indicates the post-EET surveillance paradigm. Most recurrences (75%) occur at the GEJ with the remainder in the tubular esophagus (31). In addition, although most recurrences in the esophagus are visible, most in the GEJ are not visible (51). In results from the TREAT-BE Consortium database of 50 recurrences, 74% occurred within 2 cm of the GEJ (51). In another, larger international multicenter cohort with 151 recurrences, most (74.2%) occurred at the GEJ, of which 60% were not visible, compared with those in the esophagus, of which 82% were visible. Notably, only 16% of the esophageal recurrences occurred more than 5 cm proximal to the GEJ, and none were dysplastic (33). Finally, Cotton et al. (52) analyzed 32 recurrences, and all were located within 4 cm of the GEJ. Thus, although surveillance should involve a complete and thorough examination of the entire pretreatment segment, particular attention should be paid to the distal esophagus and GEJ to detect recurrences efficiently. In addition, the rates of subsquamous BE after successful RFA are low, occurring in only 0.9% of the patients in a systematic review (53).

Risk factors for recurrence

Several factors have been associated with an increased risk of recurrence after EET. Observational studies have suggested an enhanced risk in patients with longer BE segment length, baseline HGD/IMCa, erosive esophagitis, advancing age, male sex, non-white race, smoking, and higher mean body mass index (31,35,39,54–58). In a subsequent meta-analysis that included these studies, only age (odds ratio 1.02, 95% confidence interval 1.01–1.03) and BE length (odds ratio 1.10, 95% confidence interval 1.05–1.15) significantly predicted recurrence (48). Both Ablation of Intestinal Metaplasia Dysplasia Trial data and observational studies continue to implicate baseline HGD/IMCa as associated with increased recurrence risk, suggesting that vigilance should be heightened for patients with these histologies (33,34,49).

Technical principles of endoscopic surveillance

The effectiveness of post-EET surveillance is critically dependent on meticulous endoscopic examination because most recurrences in the tubular esophagus after EET are endoscopically visible (33,51,52) but may be quite subtle. Figure 1 depicts several representative examples of the type of recurrent lesions that may be encountered in clinical practice. Awareness of the potential endoscopic appearance of recurrent BE after EET is critical to its recognition.

Figure 1.
Figure 1.:
Representative near-focus images of endoscopically visible recurrence after complete eradication of intestinal metaplasia. (a) A small island of recurrent intestinal metaplasia after radiofrequency ablation. (b) A focus of HGD partially buried beneath teh neosquamous epithelium. (c) Recurrent nodular invasive EAC several years after endoscopic eradication therapy for T1a EAC in a background of BE-HGD. (d) Recurrent multifocal low-grade dysplasia and HGD in the gastric cardia after successful EET of 5 cm BE-HGD. BE-HGD, Barrett's esophagus-high-grade dysplasia; EAC, esophageal adenocarcinoma; EEC, endoscopic eradication therapy.

Adequate surveillance endoscopy requires optimization of endoscopic visualization. Patients should be adequately sedated, with monitored anesthesia care if necessary, to avoid coughing and patient motion. The esophageal mucosa should be irrigated until all debris is removed with simethicone or N-acetylcysteine used as needed to facilitate defoaming and mucolysis. The use of a soft, transparent plastic cap mounted on the tip of the endoscope should be considered to enable en-face positioning for near-focus examination and photodocumentation of subtle abnormalities. Close retroflexion to inspect the gastric cardia should be universally performed (10). High-definition white light endoscopy (HDWLE) with the use of electronic chromoendoscopy (25) should be considered as the standard of care for post-EET surveillance (59).

Biopsy protocol

Once targeted sampling of visible abnormalities is complete, biopsies of the neosquamous epithelium and GEJ must be conducted in a systematic protocol to detect nonvisible recurrence. The most recent American College of Gastroenterology guidelines for the management of BE proposed obtaining 4-quadrant biopsies every centimeter throughout the previous BE segment with GEJ biopsies taken and placed in a separate specimen container (10).

Recent research has challenged the notion that biopsies should be taken throughout the entire extent of the pretreatment BE segment after CE-IM. As previously discussed, the overwhelming majority of recurrences occur within 5 cm of the GEJ and are endoscopically visible (33,51,52). Using a 4-quadrant biopsy protocol every cm, particularly in treated long-segment BE, can be time consuming. Indeed, the yield of biopsying normal-appearing neosquamous epithelium has been shown to be extremely low (1% for any recurrence and 0.2% for dysplastic recurrence) in a large multicenter cohort study (52). Given that adherence to preablation BE surveillance is suboptimal and (60,61) that even this extensive biopsy protocol samples only a fraction of the mucosa (62), it would likely be more efficient to devote greater time to endoscopic examination (and take targeted biopsies) than random biopsies of the normal-appearing neosquamous epithelium.

Surveillance biopsy protocols have not been prospectively or systematically evaluated. Absent consensus on a modification of current guidelines, we proposed a simplified biopsy protocol, as depicted in Figure 2. After careful inspection and taking targeted biopsies from any visible abnormalities, 4-quadrant biopsies should be taken from the top of the gastric folds (Figure 3) and placed in a separate specimen jar. This should be followed by 4-quadrant biopsies every 1 cm in the distal 2 cm of the esophagus and a set of random biopsies in the region between 3 and 5 cm above the GEJ or the remainder of the pretreatment BE segment if shorter than 5 cm.

Figure 2.
Figure 2.:
Current and proposed simplified biopsy protocols for endoscopic surveillance after CE-IM. (a) A long segment of Barrett's esophagus (C7M9 by Prague classification). (b) The conventional biopsy protocol after CE-IM with 4-quadrant biopsies taken every 1 cm. (c) A simplified biopsy protocol with 4-quadrant biopsies taken separately at the top of the gastric folds (red), in the distal 2 cm of the esophagus (green), and in the area 3–5 cm above the gastroesophageal junction (blue). CE-IM, complete eradication of intestinal metaplasia.
Figure 3.
Figure 3.:
A representative image of the location of surveillance biopsies from the top of the gastric folds after complete eradication of intestinal metaplasia.

Surveillance intervals

Surveillance intervals after CE-IM are currently guided by expert opinion because of a paucity of high-quality studies. The current American College of Gastroenterology guideline recommends surveillance on the basis of pretreatment histology (10). Patients with baseline HGD/EAC are recommended to undergo surveillance endoscopy every 3 months in the first year after CE-IM, every 6 months for the second year, and annually thereafter. For LGD, surveillance is recommended every 6 months for 1 year and annually thereafter. These recommendations somewhat mirror those for endoscopic surveillance of untreated dysplastic BE, and therefore, fail to account for the beneficial effect of EET in lowering the risk of cancer progression (18).

Recently, Cotton et al. (63) used the US RFA Registry data to build statistical models to estimate the risk of recurrent neoplasia (i.e., HGD/EAC). The model was designed to generate surveillance intervals to yield a 2.9% rate of neoplastic recurrence, corresponding to a rate of invasive EAC of 0.1% at any given surveillance endoscopy. The resulting model suggested that LGD surveillance could be lengthened to 1 year and 3 years after CE-IM. For HGD/IMCa, surveillance was recommended at 3 months, 6 months, 1 year, and annually thereafter. The model did not allow for extrapolation beyond 5 years of the follow-up. These intervals more closely match the post-EET recurrence risk and should be adopted if validated in other studies.

Currently, patients with BE achieving CE-IM are enrolled in surveillance indefinitely. Although initial reports indicated that recurrence is rare after the first year after CE-IM (34), studies with longer patient follow-up have refuted this. Sami et al. (33) recently evaluated recurrence rates for 594 patients who underwent CE-IM over a 13-year study period. This study found that the relative risk and hazard ratios for recurrence did not decrease because patients were followed up longitudinally, even when stratified by baseline histology (Figure 4). A cohort study of 260 patients who underwent CE-IM found a similar constant rate of recurrence (28). Unfortunately, the relative low number of patients at risk for recurrence in these studies beyond year 5, and low absolute number of recurrence events in these studies may obscure trends in the data. Future research is needed to determine whether patients with lower pretreatment histology (i.e., LGD) or a certain number of negative surveillance endoscopies may safely discontinue surveillance.

Figure 4.
Figure 4.:
Kaplan-Meier curve demonstrating the continuous increasing incidence of recurrence over time after achievement of CE-IM. Reproduced with permission from Sami et al. (33). CRIM, complete remission of intestinal metaplasia; HGD, high-grade dysplasia; IMC, intramucosal adenocarcinoma; LGD, low-grade dysplasia.

TREATMENT OF RECURRENCE

The management of recurrence after CE-IM has not been subjected to rigorous comparative research and is currently based on expert opinion (10). Existing studies demonstrate that nearly all endoscopic recurrences can be successfully managed with endoscopic therapy (30,31,34,42,50). However, rare cases of recurrent invasive EAC requiring esophagectomy have been reported (28,31). Endoscopic treatment of recurrence depends on the histology and morphologic characteristics of the recurrent lesion and generally reflects pre-CE-IM treatment recommendations. Areas of recurrent visible nodularity should be endoscopically resected, whereas areas of flat BE recurrence without visible nodularity can be ablated. Nonvisible recurrence should prompt a repeat upper endoscopy to closely examine for an overlooked visible recurrence. If the recurrence is not visualized, management is dependent on the histology of recurrence and is guided primarily by expert opinion. In nondysplastic nonvisible recurrence, endoscopic surveillance is reasonable. The management of dysplastic nonvisible recurrence presents a more challenging scenario. If available, advanced imaging modalities, such as volumetric laser endomicroscopy (VLE) could be attempted to localize the recurrence. Otherwise, focal ablation at the level of the biopsy showing recurrence may also be a reasonable strategy. The goal of treatment in recurrence is to again achieve CE-IM, at which point surveillance intervals should be adjusted to reflect the initial post-CE-IM paradigm. A schematic of this management strategy is depicted in Figure 5.

Figure 5.
Figure 5.:
A proposed algorithm for the management of BE recurrence during endoscopic surveillance after successful endoscopic eradication therapy. *Management of nonvisible recurrence is not well described and is guided by expert opinion. BE, Barrett's esophagus; CE-IM, complete eradication of intestinal metaplasia; EET, endoscopic eradication therapy; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.

MEDICAL THERAPY

Reflux control

Recent guidelines recommend ongoing medical antireflux therapy after achievement of CE-IM with suggested clinical endpoints of symptom control and absence of erosive esophagitis (10). This reflects observations that erosive esophagitis may enhance the risk of recurrence (54) and more than 25% of the patients with BE may exhibit suboptimal acid control despite twice-daily proton pump inhibitor (PPI) therapy (64). Komanduri et al. (38) recently evaluated the impact of reflux control on recurrence risk in 221 patients with BE enrolled in a standardized reflux management protocol. In this cohort, 22% of the patients did not achieve CE-IM in 3 RFA sessions and, of these, 79% were found to have abnormal pH testing. These patients underwent corrective action, including PPI adjustment or fundoplication, after which all achieved CE-IM. In those achieving CE-IM, only 13 experienced recurrence (6.3%) and none after 3 years. Compared with a historical control with a similar follow-up, IM recurrence was significantly reduced in the aggressive reflux management protocol cohort. These findings suggest that reflux control is important for both the achievement and maintenance of CE-IM.

Chemoprevention

An important remaining question is whether PPI therapy has a chemopreventive role in recurrence after CE-IM in patients without symptoms or erosive esophagitis. A recent large, randomized trial established the superiority of high-dose to low-dose PPI in untreated patients with BE for a composite endpoint including all-cause mortality and HGD/EAC (65). However, no such data currently exist for patients after EET. For now, in such patients, it is reasonable to continue PPIs after a discussion of the uncertainty of benefit of long-term PPI therapy (66). The role of other potential chemopreventive agents, such as aspirin and statins, has not been established in the postablation population. Given their lack of proven efficacy, their potential for associated adverse effects and the already substantial protective effect derived from successful ablation, routine use of such agents in the postablation patient is not recommended.

THE ROLE OF ADVANCED IMAGING MODALITIES

Concerns regarding sampling error and subsquamous disease after EET have generated substantial interest in the use of adjunctive imaging techniques to enhance the detection of recurrent or residual IM and neoplasia. Aside from virtual chromoendoscopy, the routine use of these techniques in endoscopic surveillance after CE-IM is not currently advocated because of limited research data, demonstrating added clinical benefit (10).

Confocal laser endomicroscopy (CLE) uses a laser light source and intravenous fluorescent contrast to produce high-resolution magnification images of the gastrointestinal mucosa that can approximate histology (67). Only a single study has evaluated the role of probe-based CLE (Cellvizio; Mauna Kea Technologies, Paris, France) in post-EET surveillance (68). In this study, 119 patients undergoing ablation were randomized to HDWLE with or without CLE and monitored for outcomes of complete eradication and recurrence. The study was halted early when no benefit of probe-based CLE was noted.

VLE (NinePoint Medical, Bedford, MA) is an endoscopic probe-based application of optical coherence tomography that allows for high-resolution wide-field imaging of the esophagus (69). The combination of high spatial resolution and imaging depth of 2–3 mm uniquely positions VLE for subsquamous imaging (70). Accordingly, VLE has been shown in case reports to detect subsquamous neoplasia not found by conventional methods (71). However, in a study of 17 patients achieving CE-IM, 13 of 17 (76.4%) demonstrated postablation subsquamous structures on VLE, only 1 of which was found to correspond to SSIM on histology (72). A registry study of 1,000 patients demonstrated that VLE identified 2 cases of recurrent HGD/EAC not detected by conventional methods and, when combined with HDWLE, demonstrated a negative predictive value of 100% for recurrent disease (73). Prospective validation of these findings could implicate a role for VLE in post-treatment surveillance. Of note, the relatively rare occurrence of subsquamous EAC in the postablation population calls into question the clinical relevance of subsquamous glandular mucosa after otherwise successful ablation.

Finally, wide-area transepithelial sampling (WATS-3D; CDx Diagnostics, Suffern, NY) is a novel technique in which an abrasive brush is used to sample the entire BE or post-treatment segment, and the tissue sample is processed by a computer imaging system and subsequently reviewed by pathologist (74). The role of WATS in post-EET surveillance has yet to be directly evaluated.

SIGNIFICANCE OF ISOLATED IM OF THE GEJ/GASTRIC CARDIA

The relationship between IM located in the tubular esophagus and GEJ/gastric cardia and their premalignant potential remains the topic of active debate. An important question is whether ablation enhances the risk of cardia neoplasia, as has been previously suggested (75). In some studies of patients after RFA CE-IM, dysplastic recurrence is seen more often in the GEJ/cardia than in the tubular esophagus (28,31,33), whereas in another study, only cardia IM without dysplasia was encountered (30). Additional studies intended to address this question have continued to present conflicting data. In a study of 149 patients undergoing RFA, 8.7% developed cardia dysplasia and EAC (44). However, in a recent study, EET was found to reduce the likelihood of cardia dysplasia from a pretreatment prevalence of 21.4%–0% at 18 months after further treatment (76). Taken together, these studies support the recommendation to sample the GEJ/cardia during post-treatment surveillance (10). Furthermore, no cardia dysplasia was seen on surveillance in a study explicitly stipulating circumferential ablation of the GEJ with the focal RFA ablation catheter (30), suggesting that this is a reasonable practice to incorporate into RFA treatment.

A second question is whether the finding of isolated IM of the GEJ/cardia during post-treatment surveillance should necessitate further treatment. In symptomatic patients without BE presenting for upper endoscopy, isolated cardia IM is present in 13% and IM of the cardia and GEJ is far more common, occurring in over 50% (77). The neoplastic potential of isolated IM of the cardia/GEJ (in those without BE) is low, as shown in at least 2 US cohort studies (78,79). However, the natural history and neoplastic potential of isolated cardia/GEJ IM postablation (which is likely distinct from GEJ/cardia IM in those without BE) is yet poorly defined. Additional data on the natural history of isolated nondysplastic GEJ/cardia IM after successful EET are eagerly awaited to enable the development of guidelines to manage this condition.

FUTURE DIRECTIONS for Novel BE detection techniques

Swallowed sampling devices, such as the Cytosponge (Medtronic, Minneapolis, MN), EsophaCap (Capnostics, Doylestown, PA), and EsoCheck balloon (Lucid Diagnostics, New York, NY) offer nonendoscopic esophageal tissue sampling (80). These techniques can be coupled to tissue biomarker testing to enhance diagnostic accuracy (81,82). Although these devices may be valuable in BE screening, their role in the post-treatment surveillance setting is not yet clear because BE recurrence occurs in very scant amounts of the mucosa.

The measurement of exhaled volatile organic compounds has also been investigated for the diagnosis of BE (83). Volatile organic compound profiles of patients with dysplastic BE who had completed EET were compared with those of endoscopy, yielding an area under the curve of 0.79 for the detection of BE (84). This “breath biopsy” technique holds promise, once validated and refined. Whether it will prove useful in the postablation setting is not yet known.

CONCLUSIONS

The number of patients requiring care after EET is expected to continue to rise, both because of the safety and efficacy of ablative techniques and the rising incidence of BE. Although dysplastic recurrence after CE-IM is relatively uncommon, overall rates are substantial, at 8%–10% per year, and may only involve small amounts of the mucosa, necessitating careful and meticulous endoscopic surveillance. Fortunately, most recurrences can be successfully managed with endoscopic therapy. A simplified biopsy protocol and somewhat attenuated surveillance intervals appear to be supported by recent research and may lessen the burden of care without harming the detection and treatment of recurrence. However, several important questions remain, including the relationship of isolated cardia IM post successful EET to esophageal neoplasia and the importance and prevalence of subsquamous disease. New technologies and scientific discoveries are likely to transform the endoscopic detection and management of BE and may fulfill the promise of a nonendoscopic surveillance paradigm. Future studies will be needed to clarify the role of new techniques and refine risk-stratification paradigms to further enhance postablation care.

CONFLICTS OF INTEREST

Guarantor of the article: Prasad G. Iyer, MD, MSc.

Specific author contributions: A.K.: drafting of the article, creation of figures, critical revision of the article for important intellectual content. N.J.S. and P.G.I.: drafting of the article; critical revision of the article for important intellectual content. All authors approved the final version of the article.

Financial support: Supported in part by NCI R01 CA 241164 (to P.G.I.).

Potential competing interests: A.K.: research equipment and unrestricted travel grant from NinePoint Medical. N.J.S.: research funding from Medtronic, Pentax, CSA Medical, Interpace Diagnostics, Lucid, CDx Medical, EndoStim, and Ironwood. Consultant: Boston Scientific and Cernostics. P.G.I.: research funding from Exact Sciences, Pentax Medical, Medtronic, and NinePoint Medical. Consultant: Medtronic, CSA Medical, and Symple Surgical.

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