Key points

The idea of natural orifice surgery (NOS) was conceived by Sergey Kantsevoy and Tony Kalloo in the late 1990s. A group of physicians got together to form the Apollo Group (Sydney Chung, Peter Cotton, Chris Gostout, Rob Hawes, Tony Kalloo, Sergey Kantsevoy, and Jay Pasricha) in 1997. Their vision and mission were to impact the practice of therapeutic endoscopy through innovation in techniques and technologies. The Apollo Group initially partnered with Olympus in an effort to accelerate product development. The concept of NOS was introduced at the initial meeting between the Apollo Group and Olympus held on Kiawah Island, South Carolina in 1998. Several acronyms for the procedure were initially proposed, with the first being flexible endoscopic surgery (FES). The original concept of FES presented by Kalloo and Kantsevoy involved per-oral passage of a flexible endoscope into the stomach followed by entrance into the peritoneal cavity via a gastrostomy. The rationale presented to support investment in the development of this procedure hypothesized that it would cause less postoperative pain, have improved cosmesis, avoid laparoscopic port hernias, and could potentially be performed in an environment less costly than a traditional operating room (OR). Kalloo and Kantsevoy worked diligently in the laboratory between 1998 and 2002 and settled on an approach that involved making an incision in the anterior wall of the stomach with a needle knife, augmenting the incision with balloon dilation, and then placing a double-balloon overtube to secure stable access to the peritoneal cavity and avoid leakage of gastric contents during the procedure. Their preliminary data on transgastric peritoneoscopy were presented to the Society for Surgery of the Alimentary Tract during Digestive Diseases Week (DDW) 2000. Their work in the laboratory eventually culminated in the historic presentation of endoscopic gastrojejunostomy presented at DDW in 2002. This work was the first demonstration that an established surgical procedure could be successfully performed entirely with a flexible endoscope through a natural orifice. The implications of FES and the potential for it to cause a significant paradigm shift in minimally invasive surgery (MIS) and therapeutic endoscopy were quickly recognized by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and the American Society for Gastrointestinal Endoscopy (ASGE). In an effort to guide the investigation and responsible development of this new approach to surgery, a joint committee was formed and chaired by David Rattner (representing SAGES) and the author (representing ASGE). The formal committee work was preceded by a meeting in New York of a working group consisting of equal representation from SAGES and ASGE. From this working group came 3 important items:

• 1.
  

  The acronym for the procedure: NOTES—Natural Orifice Transluminal Endoscopic Surgery

  
  
• 2.
  

  The acronym for the committee: NOSCAR—Natural Orifice Consortium for Assessment and Research

  
  
• 3.
  

  A White Paper—jointly published by SAGES (Surgical Endoscopy) and ASGE (Gastrointestinal Endoscopy)

The primary goal of the White Paper was to assure the responsible evolution of NOTES by providing a road map for its development. The White Paper was critically important because it carried enormous impact and influence by virtue of its support by the most important MIS and flexible endoscopic societies. The NOSCAR committee was equally important because its mission was to implement the principles and recommendations put forth by the White Paper.

The White Paper outlined the most significant obstacles to the clinical viability of NOTES. NOSCAR went about organizing an annual meeting to bring interested stakeholders together. Initially, there was significant corporate interest on the part of laparoscopic, flexible endoscopic, and accessory companies. The first NOSCAR meeting was held in Phoenix, Arizona in 2006 and perhaps the most important component of this first meeting was the formation of working groups. These working groups were charged with developing recommendations that would provide solutions to the list of obstacles to the clinical implementation of NOTES as outlined in the White Paper. Working group participants included both laparoscopic surgeons and therapeutic endoscopists (primarily gastroenterologists) who engaged in uninhibited discussion, often including frank disagreement, and openly expressed their thoughts and ideas. Each learned from the other, but because the opinions and recommendations were offered in a spirit of striving to achieve a common goal, progress was swift and steady. Research dollars flowed into NOSCAR; a research committee was established, and Requests for Proposal were established with priority going to those grants that had the greatest potential to solving issues raised within the working groups. The funds were administered through SAGES and ASGE, assuring that the maximal amount of money would go to the investigators. In looking back, although society involvement, the White Paper, the NOSCAR meetings, and the research generated were all of great importance, the most important force driving NOTES forward was the extraordinary group of physicians and surgeons who were brought together by the singular mission to responsibly develop NOTES. The enduring friendships and ongoing collaborations between therapeutic endoscopists and laparoscopic surgeons will be an important lasting legacy of the initial NOTES movement, and it is this group that created the foundation and brought to life the New NOTES .

As time progressed, many of the perceived “obstacles” to the clinical implementation of NOTES dissolved when targeted research studies were completed. Many began thinking that NOTES could become a reality. Two philosophies emerged about how the development of NOTES should proceed. Some advocated for a slow developmental course with the initial aim being to try to address unmet needs. Another camp thought that further progress in NOTES would require a “killer application.” This idea caused surgeons to recall that “as goes cholecystectomy, so goes general surgery.” Investigators began working on transgastric cholecystectomy, and after discovering how difficult it was with existing flexible scopes and accessories, surgeons moved to transvaginal cholecystectomy (strictly speaking “a natural orifice” but one that was already well established by our gynecologic colleagues and “naturally” excluded approximately 50% of patients). Surgeons found that transvaginal cholecystectomy could be safely accomplished if they had a good understanding of principles of safe vaginal access and closure and used long rigid laparoscopic tools. Multiple dynamics were now strongly influencing the development of NOTES, and these influences would fundamentally change the direction of development and lead to “New NOTES.” These dynamics included the following:

• 1.
  

  It was becoming apparent that surgeons were frustrated with the limitations of the flexible endoscope as the platform for NOTES. They desired the cutting/hemostasis, suturing, and triangulation capability familiar to them with laparoscopic surgery. As a result, surgeons moved strongly toward transvaginal cholecystectomy, and this opened the door to the development of single-port surgery. Both approaches held the potential for less invasive access and improved cosmesis. The development of single-port surgery had a damaging effect on NOTES because it carried away valuable resources provided by laparoscopic companies (who saw greater potential for sales with single-port surgery), and it also further alienated gastroenterologists.

  
  
• 2.
  

  The movement toward use of laparoscopic instruments to accomplish a less invasive cholecystectomy had many negative ramifications for NOTES. It alienated gastroenterologists, who thought that NOTES was being high-jacked and excluded their continued participation. The move toward cholecystectomy was ill conceived because the margin to improve the procedure over standard laparoscopic cholecystectomy was so small that it would never be widely adopted.

  
  
• 3.
  

  With the demise of the grand dream of NOTES and the evolution toward new approaches to laparoscopic surgery, corporate money was redirected from NOSCAR to internal development and promotion of each company’s vision for single-port surgery.

  
  
• 4.
  

  In the opinion of this author, the final “nail in the coffin” for NOTES occurred when a decision was made to increase corporate funds for a randomized trial between standard laparoscopic and NOTES cholecystectomy. Industry had become skeptical that NOTES would be widely adopted, and without the support of industry for research and device development, the evolution of NOTES could not be realized. It was thought that if it could be demonstrated that a “killer app” procedure could be safely and effectively done with an NOTES approach, that this would reinvigorate the industry and the medical/surgical community and re-establish the NOTES movement. NOSCAR members advised that transgastric cholecystectomy could be done, and transvaginal cholecystectomy had now become reasonably well established. A multicenter, randomized, noninferiority study was designed comparing laparoscopic with transgastric and transvaginal cholecystectomy. Industry money was secured for the trial; very innovative mechanisms were developed for malpractice coverage and to cover extra costs to the institution, and the trial was begun.

The cumulative effect of these events essentially ended (for the present) the NOTES movement as it was originally conceived by Kalloo and Kantsevoy. The flexible endoscope was not embraced by surgeons, in part because of the lack of effective accessories. Most gastroenterologists (who had the greatest expertise and knowledge of therapeutic endoscopy) had become marginalized; industry money was gone. Research had come to a standstill, and the only tangible evidence of the original NOTES was the annual NOSCAR meeting, which now was run on a shoestring budget but still attracted this very special group of MIS and therapeutic endoscopists who had formed an unbreakable bond and came together with the singular purpose of moving minimally invasive therapy forward.

To understand the development of New NOTES, one has to first understand the state of the evolution of the original NOTES concept (outlined above) and then go back to the Apollo Group. It was the brilliance of Chris Gostout and his group working in the Mayo Clinic Developmental Endoscopy Unit that initiated the journey toward New NOTES. In 1998, they began working to solve the riddle of safe and easy en bloc resection. This work slowly evolved over a decade but was accelerated in 2005 when Kazuki Sumiyama, an advanced endoscopy Fellow from Jikei University in Tokyo, joined the team. Three very important concepts emerged from the work of Dr Gostout and his team: (1) the concept of tunneling to create a submucosal space; (2) the idea that the submucosa could be “opened” to create a working space (submucosal endoscopy, submucosal surgery, third-space surgery); and (3) the concept of safe closure using a mucosal flap. Their work with submucosal tunneling came about from their experience with creating a space by tunneling through the submucosa. They then went on to conceive that by making an incision through the muscularis propria and serosa at the end of the tunnel; they could accomplish safe entry into the peritoneal cavity as well as safe closure using the mucosal flap. They called this “tunneled offset viscerotomy.” Their work on creating a submucosal working space came about from their desire to improve the technique of en bloc resection. Their concept was called Submucosal Inside Out Project, in which they lifted a lesion, made a mucosal incision, dissected the submucosa underneath the lesion to create a working space, and then made the circumferential incision from inside the submucosal space toward the gut lumen, thus avoiding any chance of perforation. Gostout’s group began work on transluminal mediastinal access in parallel with their work on peritoneal access. They found that their tunneling technique had great appeal when working in the esophagus, and it was from this work that they discovered the value of the mucosal flap. They found that they could safely tunnel down the esophageal submucosal space, incise the muscle layer, enter the mediastinum, and then withdraw the scope and achieve safe and effective closure by simply clipping the small mucosal incision.

By virtue of being a member of the Apollo Group, Jay Pasricha was aware of Dr Gostout’s work in submucosal tunneling. Pasricha’s innovative mind combined with his knowledge of motility disorders and therapeutic endoscopy led him to conceive of the idea of performing a submucosal tunnel to facilitate a myotomy in the treatment of achalasia. He used the tunneling and flap closure technique outlined by Gostout and Sumiyama and thought that the myotomy could be as effectively performed from within the submucosal space. Dr Pasricha did the preliminary work in pigs and published this idea in 2007. The work of Drs Gostout, Sumiyama, and Pasricha was noted by Dr Haruhiro Inoue, who was working in Yokohama. In retrospect, Dr Inoue was the ideal person to further develop Dr Pasricha’s idea. Dr Inoue is trained as a foregut surgeon and was, and still is, active in MIS of the esophagus, including Heller myotomy. Dr Inoue is also an internationally recognized expert in flexible endoscopy and is known for his work in endoscopic mucosal resection and endoscopic submucosal dissection (ESD). Taking the idea of Pasricha and leveraging his skill as a foregut surgeon and ESD expert, he brought Dr Pasricha’s idea to clinical fruition and named the procedure per oral endoscopic myotomy (POEM). He published his first series of POEM in 2010.

In many respects, the development of POEM was a benevolent “perfect storm” for the NOTES movement. It was a procedure that required excellent endoscopic skills and could be performed by surgeons and gastroenterologists. It represents an endoscopic procedure performed through a natural orifice that has the potential for replacing an accepted standard surgical procedure (Heller myotomy). It also fulfilled one of the promises of NOTES in that it brought the procedure from the OR to a less costly environment within the endoscopy suite. It also brought to clinical reality Gostout’s original idea of third space (submucosal) surgery. The success of POEM has now provided a basis for endoscopic full-thickness resection techniques (submucosal tunneling endoscopic resection) being applied to small stromal tumors and potentially for endoscopic pyloromyotomy.

In retrospect, Kalloo and Kantsevoy’s vision of NOTES was perhaps too far ahead of its time. Very few surgeons had the requisite endoscopic skills; gastroenterologists were not in a position to perform traditional surgical procedures. Available endoscopic devices were in the dark ages compared with laparoscopic instruments, and industry was not prepared for a systematic, well-organized, long-term investment to allow NOTES to be responsibly developed. The obstacles to NOTES had to be systematically studied and resolved; devices had to be developed to enable safe and effective outcomes, and time was needed to allow these new techniques to be applied first in cases of unmet needs to allow refinement to optimize outcomes before competing with standard surgical procedures. Gostout’s vision of creating an operating environment within the submucosa and the effectiveness of the mucosal flap closure, Pasricha’s vision of NOS using the flexible endoscope for the treatment of achalasia, and Inoue’s remarkable work to make POEM a standard procedure around the world have come together to create a discipline some are calling New NOTES . The development of these New NOTES procedures establishes a very important basis from which further development can proceed and serves as a bridge to true NOTES. It demonstrates to the industry the potential of the flexible endoscope through a natural orifice. Procedures can now evolve at a responsible rate, and industry can invest in new device development with a reasonable assurance that they can obtain a return on investment. As experience grows in submucosal surgery, confidence will build that mucosal flap closure is reliable. These techniques combined with new technologies may provide the segue into transesophageal mediastinal or transgastric peritoneal exploration that will ultimately lead to the clinical application of true NOTES as originally envisioned by Kalloo and Kantsevoy.

It has now been almost 20 years since the initial concept of NOTES was presented by Kalloo and Kantsevoy. Their vision has followed a somewhat traditional course that began with exuberant enthusiasm (usually too optimistic) and then morphed into tempered optimism. This phase was followed by a time of discouragement when unanticipated problems were encountered. Working through the discouraging times is dependent on the group of true believers who are invested for the long haul. In the opinion of this author, we have emerged from the discouragement phase and are now in a position to move forward toward true NOTES. In part, this is due to the bridging techniques of New NOTES but also to the work of some of the faithful. The careful and systematic investigative work of Lee Swanstom, Patricia Sylla, and Antonio Lacy on transanal colon resection is coming to fruition, and this will likely be recognized as the first NOTES procedure to cause a paradigm shift in surgery. Optimism that true NOTES will be a broad clinical reality has now re-emerged. The course is set, and the ultimate success of NOTES will be attributed to the pioneering idea of Kalloo and Kantsevoy, the concepts of Gostout and Pasricha, the pioneering work of Inoue, but perhaps most importantly, the remarkable collaboration worldwide between minimally invasive surgeons and therapeutic endoscopists who have formed a cohesive community with a common goal of developing less invasive therapies to benefit patients.