Perhaps in no other field does the word innovation characterize a discipline than in the field of surgery. Whether it was the introduction of anesthesia in the Ether Dome at Massachusetts General Hospital in 1846 or the first heart transplant in 1967 in South Africa, surgeons have continued to push the limits of how surgical pathology is addressed. This emphasis is best illustrated with the historical progression toward antisepsis and contemporary anesthetic techniques. It is not without these significant developments that the field of surgery was able to address electively more advanced pathology, without a prohibitive risk to the patient.

Much like the progress made in the appreciation of antisepsis, sterile technique, and anesthesia, the practice of surgery has undergone a significant evolution in the past two centuries. One of the most noteworthy developments has been the increasing emphasis placed on minimizing the physiologic insult to which the patient is exposed. This surgical tenet is best supported by the adoption of laparoscopic surgery. By moderating the surgical trauma through laparoscopy, the impact on the systemic immune system is less than that in case of a laparotomy.¹ Minimally invasive techniques now form the foundation of modern surgical techniques to the extent that open operations are rarely the first approach to the majority of surgical pathology.

Much of the framework upon which modern laparoscopic technology is based was developed over two centuries ago by the founders of endoscopy and their desire to explore internal organs using a minimally invasive methodology. The first endoscopies were performed by Phillip Bozzini in 1805.² Using a novel device constructed from a steel tube and illuminated by candlelight, he completed the first cystoscopies using a canine model. It was not for another 50 years that the first therapeutic cystoscopy was performed on a human patient. However, the use of turpentine and alcohol as a light source was associated with significant thermal complications, limiting its widespread use. It was because of these deficiencies and lagging support by medical professionals that the first laparoscopic exploration did not occur until 1901, almost a century after Bozzini introduced the concept. Within a decade, this technology had transitioned to a human model, using a cystoscope to visualize intra-abdominal pathology.

Notwithstanding the potential of these new techniques, general surgery was slow to adopt laparoscopy. There are many contributing factors for this resistance. Early laparoscopic efforts were complicated by increased morbities to which the patient is exposed.² For many general surgeons, this proved to be prohibitively dangerous for the introduction to personal patients. Additionally, there was a clear deficiency in the optics and ergonomics of a laparoscopic approach. Many of the initial operations were performed using independently developed instruments that obligated the surgeon to stoop over a single viewing laparoscope.³ It was not until an American gynecologist attached the laparoscope to the end of a video camera, suspending the pair from the ceiling using a duct tape, that the video laparoscopic procedure was realized. Despite the prospect of once again being able to work as a surgical team, general surgery persisted in its resistance to this technology. As late as 1987, when Phillip Mouret performed the first video laparoscopic cholecystectomy, naysayers still outnumbered the advocates.⁴ It was not until industry and patient preference began to champion laparoscopic surgery that the shift to minimally invasive techniques began in earnest. Within a decade laparoscopic approaches had been described for everything from a simple cholecystectomy to adrenalectomies and colectomies.

In an effort to move laparoscopy forward, early pioneers in the field endeavored to decrease the invasiveness of the approach. This is best illustrated by Pelosi and Pelosi’s⁵ description of a single-incision laparoscopic approach in 1992. This new concept was coined as single-incision or single-site laparoscopic surgery (SSLS). SSLS initially suffered from the same limitations that plagued early laparoscopic efforts. The ergonomics of a single-incision technique proved to be prohibitively cumbersome for most surgeons. This changed with the introduction of SSLS-specific ports, facilitating the use of multiple instruments through a single fascial defect.^6,7 This new technology reinvigorated the technique, making SSLS a legitimate option for many common surgical procedures.

In 2004, the next permutation in minimally invasive techniques was introduced by Kalloo et al⁸ in their description of transgastric diagnostic peritoneoscopies completed in a porcine model. This new approach was coined as natural orifice translumenal endoscopic surgery (NOTES). In response to this work and unpublished international reports, leaders in the fields of gastroenterology and surgery formed the ASGE/SAGES Working Group on Natural Orifice Translumenal Endoscopic Surgery. Recognizing the potential ramifications of the unchecked widespread adoption of this new technique, this group drafted a White Paper.⁹ This document identified several limitations to NOTES that needed to be addressed prior to its generalized application outside of a clinical trial. These issues included the ability to access the peritoneal cavity safely, the physiologic and infectious implications of an approach through a natural orifice, and platform development and anastomotic devices.

Since that time many of these questions have been addressed in both animal and human models. The ability to access safely the abdomen from a transgastric, transcolonic, and transvaginal (TV) approach has been documented in human models. The safe, standalone insufflation of the peritoneal cavity has been validated in controlled trials in a human model using a transgastric approach in patients without consideration for the type or number of previous abdominal operations.¹⁰ The risk of contamination has been evaluated in both human and animal models using TV and transgastric approaches.¹¹–¹⁸ In each study, the risk was noted to be nominal and without sufficient grounds to deter the approach. Platform development persists as the rate-limiting step in the adoption of the technology by the community general surgeon. Concurrent with the work addressing the limitations outlined in the White Paper was an effort to identify potential operations that can be completed using a natural orifice approach. Using principally animal models, numerous operations were described, including bowel anastomoses, solid organ resection, hernia repairs, and diagnostic explorations.¹⁹–²⁵

The necessary next step in the progression of NOTES following Kalloo’s seminal article was the introduction of the concept in humans. An underlying issue to this proposal is the question of what approach should be used to access the peritoneal cavity. Diagnostic and therapeutic endoscopy in the setting of foregut pathology is a well-established technique. Further, a safe methodology for the blind transgastric approach to the abdominal cavity was described by Gauderer and Ponsky²⁶ with their description of the percutaneous endoscopic gastrostomy tube. Given this, incorporation of a gastrotomy into a NOTES protocol was a natural evolution. Preliminary studies completed at the Ohio State University confirmed the feasibility and safety of this approach in human models.²⁷ The ability to insufflate the abdomen using an endoscope has also been documented to be safe and effective in humans.¹⁰ To date, the largest series of transgastric procedures were documented by Zorron et al²⁸ in their description of 43 hybrid cholecystectomies and appendectomies during which laparoscopy was used to assist a predominantly endoscopic operation (Table 1). Outside of the early proof of concept work completed at the Ohio State University, investigations within the Unites States have lagged behind the international experience. A current search of the literature has yielded only a series of four transgastric cholecystectomies reported by Auyang et al²⁹ and a single transgastric appendectomy performed by Horgan et al.³⁰ Currently, no system or technique is available for the standalone endoscopic closure of the defect outside of an Institutional Review Board-approved investigational device study. This is significant because in the absence of a primary therapeutic operation that would otherwise require the creation of a gastrotomy, the defect created for NOTES procedure must be closed with currently available laparoscopic techniques. Without additional platform development, transgastric NOTES protocols will struggle to gain momentum outside of the selected institutions involved in device development.

Safe TV access to the abdominal cavity was introduced almost two centuries ago by Konrad Langenbeck with his description of a TV hysterectomy.³¹ Prior to the introduction of the NOTES concept, case reports established the TV approach for the removal of surgical specimens.³² It is because of the ability to access safely the peritoneal cavity and then close reliably the colpotomy that the majority of NOTES cases performed have exploited the TV methodology. To date, the preponderance of cases completed have been cholecystectomies.³³ Given the importance of patient safety and the deficiency of a validated platform for ligation of the cystic duct and artery, the majority of procedures have been completed using a hybrid approach using both transfascial and TV trocars. In most cases, a single 5 mm transumbilical port and an SSLS TV port placed through the posterior fornix are used for access to the peritoneal cavity. While the exact operative technique varies by institution, the majority of cases are performed with a single flexible endoscope and bariatric length laparoscopic instruments. The endoscope is used to dissect out the critical structures within the triangle of Calot.²⁸ Alternatively, the flexible optics of the endoscope can be used for visualization of dissection performed through a TV trocar. Some have performed the operation using strictly laparoscopic techniques completed from a TV approach.³⁴ In each case, the specimen is removed transvaginally and the colpotomy is closed externally.

As with the literature on transgastric NOTES, most of the data generated on the TV approach are internationally derived. To date, the largest published series of TV NOTES procedures is a cohort of 572 cases performed in Germany. Of these operations, 85.3% were completed for the treatment of gallbladder pathology.³⁵ Additional reports have been published describing as many as 240 TV cholecystectomies.²⁸ There are also data on diagnostic peritoneoscopies and sigmoidectomies, but in far fewer numbers than with the treatment of gallbladder pathology.³³ Perhaps the most significant publication supporting this technique was a retrospective matched-pair analysis of 200 patients comparing the hybrid TV approach with a single 5 mm transumbilical port to a classic four-trocar laparoscopic cholecystectomy. In this report, the authors noted no significant difference in morbidity, patient satisfaction, or incidence of dyspareunia. The only difference noted in this study was a 17-minute increase in the operative time for those procedures completed transvaginally.³⁶ Similar prospective studies have compared classic laparoscopic techniques to a hybrid TV cholecystectomy.³⁷ In each case, the findings of the aforementioned article by Zornig et al have been corroborated.

Owing to the decreased potential morbidity of a TV approach, research on it within the United States has progressed at a faster rate than that on the transgastric technique. However, the number of published reports remains low, with the largest published American series reporting only 14 patients (Table 2).³⁴ Similar to the data published outside of the United States, the majority of American cases have been completed using a hybrid technique. Two institutions completed studies comparing the outcomes of the TV methodology to classic laparoscopy.^34,38 Mirroring the findings of the international investigations, the only significant difference between the two approaches was operative time. It should be noted that a prospective multicenter trial (sponsored by the Natural Orifice Surgery Consortium for Assessment and Research) comparing a NOTES cholecystectomy to a classic laparoscopic cholecystectomy (www.ClinicalTrials.gov Identifier NCT01171027) is currently underway. In each case, the participating institutions were obligated to demonstrate a significant expertise and level of commitment to the NOTES technique. The trial is set to enroll approximately 200 patients prior to completion. An additional clinical trial conducted at Yale compared 18 patients undergoing a pure NOTES TV appendectomy to 22 patients undergoing a classic three-port appendectomy.³⁹ In this study, the TV NOTES approach was associated with statistically significant less postoperative analgesic use and shorter time for convalescence. These controlled, prospective trials provide the best opportunity for NOTES to gain momentum in the United States as a viable alternative to classic laparoscopy.

It is clear that a TV approach for NOTES procedures is safe. However, it is not without its limitations. Obviously, this approach is applicable only to half of the population. Furthermore, research investigating patient and physician preference is inconsistent at best. A review of the six surveys currently available in the literature shows that as few as 25% and as many as 68% of women surveyed would prefer a NOTES technique over classic laparoscopy.⁴⁰–⁴⁵ Those who responded negatively voiced concerns over a negative impact on sexual function and fertility. Conversely, patients who were interested in NOTES noted improved cosmesis, decreased pain, and reduced risk for hernia formation as appealing characteristics. Perhaps most compelling is a publication by Tsin et al⁴⁶ surveying 42 patients who underwent a TV cholecystectomy in Mexico and Cuba. Uniformly, patients were satisfied and would recommend the approach to others. When considering the two studies completed within the United States, the findings remain inconsistent. The survey completed at the Mayo Clinic found that the interest in NOTES varied depending on the operation being performed. Sixty-eight percent were likely to agree to a TV tubal ligation versus only 43% for an appendectomy or 41% for a cholecystectomy.⁴³ A study completed out of University of California, San Diego (UCSD) included a brief description of NOTES and laparoscopic approaches that were read prior to survey completion. In this well-designed experiment, women were much more likely to express interest in NOTES (73%), with the majority (68%) preferring a TV technique if data documented equivalency of the two approaches.⁴⁵ Certainly, results from individual surveys should be interpreted with a degree of skepticism. However, the available data should not deter further NOTES investigations. In particular, the study by Peterson et al verifies that education on the technique is critical for recruitment in NOTES and its success in general.

The power of patient preference to drive the surgical market was clearly displayed with the almost overnight adoption of laparoscopy for the treatment of biliary pathology. A lack of patient enthusiasm for TV NOTES procedures may ultimately limit the adoption of this technique. It is interesting that the major limiting factor for the acceptance of TV NOTES is the anxiety over infertility and its adverse effects on sexual function. These concerns have successfully been dispelled in the gynecologic literature. Perhaps this group is steadfast with the aversion to an elective TV procedure regardless of the risks. Alternatively, demonstrating the benefits of a TV approach may convince critics that a NOTES procedure is a viable alternative to classic laparoscopy.

Notwithstanding the reports in animal models of successful transcolonic NOTES procedures, this approach is a daunting enterprise for patients and surgeons alike. The morbidity of peritoneal contamination or an anastomotic dehiscence from an elective colotomy is considered prohibitively high to most physicians. With that said, many physicians are facile with the colonoscope, and a transcolonic exploration does provide for unimpeded access to the majority of the abdominal cavity. In the setting of a process for the safe closure of this opening, the transcolonic technique has promise. It is with this in mind that the concept of incorporating the colotomy or prototomy associated with a NOTES colorectal resection into the coloanal anastomosis was described. The concept of melding NOTES and transanal endoscopic surgical techniques to perform a rectosigmoid resection was first evaluated in a swine model.²⁵ In these proof-of-concept studies, a combined transgastric and transanal approach provided for significantly more mobilization of the rectosigmoid colon as well as a significant increase in the length of specimen resected. Following extensive laboratory work with both swine and human cadavers, this technique was recently performed in humans for the first time (Table 3).⁴⁷ In this case, a successful NOTES transanal endoscopic rectosigmoid resection, using transanal endoscopic surgical technique and laparoscopic assistance, was completed in a 76-year-old woman with a T2N2 midrectal cancer. Through the incorporation of needlescopic ports and transrectal specimen extraction, the only fascial defect was incorporated into a diverting loop ileostomy. Since this seminal case, five additional cases of transanal endoscopic rectal cancer resection with laparoscopic assistance have been completed successfully in the setting of an IRB-approved clinical trial in the United States (www.ClinicalTrials.gov Identifier NCT01340755). Currently, there is a paucity of data regarding this approach within the United States. Internationally, a report published by Lacy et al⁴⁸ described a hybrid approach to complete a total colectomy trans-rectally with the assistance of three laparoscopic ports. Zorron et al⁴⁹ and Chen et al⁵⁰ have also reported three hybrid colorectal excisions with transanal NOTES mesorectal dissections. To date, a description by Tuech et al⁵¹ remains the only documented case paralleling our experience during which a single additional port used for left colonic dissection is incorporated into the diverting ileostomy. We feel that this is a promising application of NOTES in the field of colorectal surgery that successfully unites transanal endoscopic surgery with a NOTES approach.

Currently, there is a small niche that makes up the transrectal and transcolonic NOTES experience. Incorporation of this approach outside of a procedure that necessitates a colonic resection is prohibitively dangerous for many. With that said, the aforementioned procedures take the TV work one step closer toward a true NOTES procedure with the exclusion of unnecessary fascial defects. We feel that this work is vital to the field of NOTES and has great promise for the minimally invasive treatment of colorectal pathology.

Perhaps, the best example of a standalone NOTES procedure is the pioneering work of Inoue et al⁵² in the treatment of achalasia. Classically, this pathology is addressed medically or with endoscopic dilation of the gastroesophageal junction (GEJ). Refractory cases may be addressed surgically with a laparoscopic Heller myotomy and concomitant partial fundoplication. The incorporation of a fundoplication is necessitated by the crural dissection performed to expose the GEJ for myotomy creation. Dr Inoue hypothesized that because of the diseased nature of the esophagus, a fundoplication may be avoided in the absence of a crural dissection. With that in mind, he developed a true NOTES approach for the creation of an esophageal myotomy. In this procedure, a standard therapeutic endoscope with a transparent cap was used. With the patient under general anesthesia, a needle knife is used to create an endoscopically fashioned submucosal tunnel from the midesophagus down across the GEJ. Starting 3 cm below the mucosal defect, dissection of the circular muscle is completed in a similar manner. Paralleling the tenets of a laparoscopic approach, a long myotomy is created that extends down across the GEJ onto the fundus of the stomach. The mucosa is then reapproximated with standard endoscopic clips. In the initial publication, 17 patients with medically refractory achalasia were treated with this peroral endoscopic myotomy (POEM). In each case, the dysphagia symptom score and resting lower esophageal pressure decreased significantly post procedure. Further, there were no significant procedure-related complications in this small case series. Mirroring the rest of the NOTES field, a select number of groups are performing this procedure on approved IRB protocols within the United States. Currently, however, little data have been published. Swanström et al⁵³ reported the only currently available American study on POEM to date. In this trial, five patients successfully underwent POEM without any complications and with good short-term symptom resolution. Long-term studies are necessary to establish the risk of postprocedure gastroesophageal reflux disease and the complications that will arise when performed by multiple practitioners. With that said, this approach is a promising example of the potential that natural orifice surgery possesses.

Throughout its history, the practice of surgery has emphasized the concept of innovation in the way that surgical pathology is addressed. Beginning with the pioneering work of the founders of endoscopy and laparoscopy, surgical approaches have striven to minimize the potential morbidities to which the patient is exposed. Natural orifice translumenal endoscopic surgery promises to be the next permutation in the minimally invasive treatment of surgical diseases. With that said, it is a field that is still in its infancy. It is only with a continued emphasis on platform development and well-designed clinical trials that the true potential of this new field will be realized.