Once in a few decades in science or medicine, an idea emerges that is so powerful that it changes forever how we think about that field. Natural Orifices Translumenal Endoscopic Surgery (NOTES) has the potential to break the physical barrier between bodily trauma and surgery.

At the dawn of surgery, excellence was associated with big incisions: “big scar – big surgeon”.

In the 80s, minimally invasive surgery was born representing one of the greatest surgical evolutions of the 20th century. After Kalloo’s first report in 2004 on transgastric peritoneoscopy in a porcine model, the interest in natural orifice transluminal endoscopic surgery (NOTES) has blossomed. Theoretically the same operation performed laparoscopically could be carried out through natural orifices without any abdominal incision avoiding pain and scarring. The lesson learned from the advent of laparoscopic surgery, thought us that we could be witnessing the birth of another surgical revolution.

Since 2004 many abdominal procedures that use a NOTES approach have been successfully performed in animal models. However, the initial excitement for NOTES has been somewhat tempered by the reality that a NOTES procedure in human without laparoscopic assistance has not been performed by most groups. Indeed, a major issue is the lack of stable operative platform and flexible instruments that allow retraction and exposure of the organs, such as appendix or gallbladder. Will this issue change the future of NOTES?

Originally created as a diagnostic tool, flexible endoscopy has evolved over the past decade to become more therapeutic in nature. Several advanced therapeutic techniques have been reported, with many being incorporated into routine clinical practice over time, including endoscopic mucosal and submucosal dissection, endoscopic suturing for GERD, and, more recently, natural orifice transluminal endoscopic surgery (NOTES). This complex technique involves breaching the wall of the stomach, colon, or vagina by endoscopic means to gain access into the peritoneum to perform the desired therapy. There are a number of potential benefits to using NOTES over traditional surgical techniques that are associated with the lack of surface incision, including the elimination of surgical site infections and any visible scarring, a reduction in pain and the need for anesthesia and analgesia, recovery time, hernia formation and adhesions, and the ability to perform procedures in patients where an abdominal incision is difficult such as in the morbidly obese.

Few endoscopists in the past would have dared to breach the GI lumen on purpose. Percutaneous endoscopic gastrostomy was the first surgical endoscopic technique that intentionally perforated a hollow organ(1). Following this, transluminal drainage of post-pancreatitis collections progressively accustomed some endoscopists to an extra-luminal approach(2). The first to have used a surgical endoscopic technique for the resection of an organ’s segment, and as such an opening to the peritoneal cavity, is G. Buess, who described in 1984 transanal endoscopic surgery(3). Complete resections of low sigmoid or rectal tumours with parietal defect suturing are performed through an adapted rectoscope using specific instrumentation.

After Kalloo’s first report in 2004(1) on transgastric peritoneoscopy in a porcine model, the interest in NOTES has blossomed. This article sparked enthusiasm in the medical community but also in the surgical community. Theoretically the same operation performed laparoscopically could be carried out through natural orifices without any abdominal incision. The lesson learned from the advent of laparoscopic surgery, thought us that we could be witnessing the birth of another surgical revolution.

Although most believe after Kalloo’s report(1) that the peroral route will be the one to dominate NOTES in the future, today there are still several difficulties performing transgastric NOTES techniques with the instruments currently available, A factor limiting the transgastric route is the lack of a secure and reliable method for creating and closing the gastrotomy required by the procedure. Indeed, creating a gastrotomy from within the stomach requires a blind entry to the peritoneal cavity making it hard to both avoid damage to neighbouring structures(2) and ensure the gastrotomy is sited in the best possible position. The value of endoscopic ultrasonography to overcome these issues is under evaluation(3).

Several gastrotomy techniques have now been described. The most used technique is based on the established safety of percutaneous endoscopic gastrotomy (PEG) placement with ballon dilatation(4). A flexible wire passed through the anterior abdominal wall guides the stomach incision and dilatation of the gastrotomy. Another seductive approach is the submucosal flap technique. An incision is first made in the gastric mucosa. The submucosal space is developed and a tunnel of at least 5 cm length is created using a dissecting balloon(5) or EMR-cap(6). After tunneling away from the mucosal defect, the muscularis and serosa are punctured, and the abdomen is entered. At the end of the procedure, the scope is withdrawn, the myotomy site is sealed with the overlying mucosal flap, and only the mucosa is closed.

Closure of the gastrotomy is indeed crucial. Although in some early studies, the gastrotomy performed with baloon technique was left open, there is now general agreement that there must be near-zero tolerance for leaks. The ideal closure should be rapid, reproducible, and safe, ideally performed under vision to avoid any injury to the adjacent organs and should grant a full thickness bite. In addition a method that is easily reproducible and inexpensive is highly desirable. Different methods have been reported in the literature mainly presented from the endoscopist’s side with endoclips representing the most commonly used method of closure(7,8). However, the simple application of mucosal clips enables only a single-layer tissue approximation and is best suited for small defects and could be used in emergency situation to close an accidental minute endoscopic perforation.

Different techniques have been reported in the literature with variable results and success rates but majority of these at present remain experimental and are not widely available. Original techniques using a cardiac septal occluder(9), surgical stapler(10), transparietal tags(11), bioabsorbable plugs(12) were described. Using two endoscopes to provide layer-by-layer endoscopic clip closure is another alternative that uses current endoscopic instruments(13).

While secure closure of the gastric access site is critical and difficult, transvaginal access, a route well known to gynaecologists, de facto overcomes these problems. The experience by gynecologists performing transvaginal procedures has demonstrated safety also in regards to rarity of pelvic infection or injury of adjacent organs. In addition closure of the colpotomy is performed under vision using standard surgical techniques. Additional advantages are a straight shot when targeting organs in the upper abdominal quadrants and, the fact that the colpotomy allows the use of rigid laparoscopic instruments at the side of the scope that could assist in different steps of the procedure. The removal of surgical specimens through an incision of the posterior fornix is frequently performed after different laparoscopic procedures instead of using more morbid large incisions of the abdomen or flank as required previously.

Direct access to the access site is also an advantage of the transanal route. Transcolonic NOTES has been the least explored approach to the peritoneal cavity because of concerns related to faecal contamination and intra-abdominal infectious complications. The benefits of transcolonic access include in-line endoscopic visualization, the ability to create and close the colotomy with existing transanal endoscopic microsurgery (TEM) equipment, and suitability of both male and female patients.

The next question to be addressed is whether natural orifice access can be extended into other body cavities and, in particular, whether there is a significant role for NOTES above the diaphragm using the esophagus as a direct carrier to access the mediastinum and the pleural cavity. Transesophageal endoscopic mediastinoscopy, lymph node resection, thoracoscopy, and pleural biopsy have been reported feasible and providing excellent visualization of mediastinal and intrathoracic structures in the experimental setting.

A wide range of NOTES procedures of varying complexity have been described in the experimental setting: peritoneoscopy(1,14–16) liver biopsy, lymphadenectomy(17), tubal ligation(18), oophorectomy(7,19), partial hysterectomy, cholecystectomy and cholecystogastrostomy(20,21), gastrojejunostomy(22), coelctomy, distal pancreatectomy(23) splenectomy(24), pleural biopsy, esophageal myotomy, pericardial window, sentinel node detection performed through the different natural orifices. Cholecystectomy has been extensively evaluated and it has been performed through all possible natural orifices. Ex vivo, in vivo, survival and non-survival studies have demonstrated good initial results in the animal model.

It is difficult today to speculate about the clinical outcome of most of these studies.

They served as a basis for the clinical implemention by providing training and pertinent information on the most sensible issues of NOTES, such as access and closure techniques, manipulation of the endoscope in the peritoneal cavity, spatial orientation, techniques of dissection, exposure, retraction and tissue approximation.

The major highlight of this experimental work is the inadequacy of the flexible endoscope as a platform for performing NOTES procedures. Mixed technologies using transabdominal technologies were evaluated to facilitate the NOTES procedures and the translation to human. These techniques are called “hybrid” in opposition to “pure” NOTES procedures in which only flexible tools are used without any transparietal assistance.

Clinical Setting

Initial excitement for NOTES has been somewhat tempered by the reality that a NOTES procedure without laparoscopic or needleoscopic-assistance has not been performed by most groups. Indeed, a major issue is the lack of stable operative platform and flexible instruments that allow retraction and exposure of the organs, such as appendix or gallbladder.

Initial pure NOTES transgastric procedures were gastric “PEG” rescue for a patient whose PEG tube was dislodged(25) and peritoneoscopy performed at the time of operative staging of pancreatic tumors(26) or gastric by-pass(27). Rao et al reported transgastric appendectomy, tubal ligation and liver biopsy(28).

Hybrid transgastric cholecystectomy was first performed by Swanstrom in USA and a comparable technique was presented by Auyang et al. (29). The authors utilized a new endoscopic platform, the Transport (USGI, USA) that admits large flexible instruments and a suturing device, the G-Prox (USGI, USA), to close the gastrotomy. An initial series of cholecystectomies performed with current endoscopic instrumentation was reported by Dallemagne et al. (30). Peritoneal access is gained using a needle-knife cautery and balloon dilation under laparoscopic visualization Figure 1. Tansparietal assistance for exposure and application of laparoscopic clips is provided by one or two laparoscopic trocars. Dissection of the critical view of safety is performed endoscopically Figure 2. The cystic duct and artery are clipped laparoscopically. The gastrotomy is closed laparoscopically. The gallbladder is extracted out the mouth. All the authors concluded that in order to perform a pure NOTES transgastric cholecystectomy, a safe blind access method, improved retraction, endoscopic hemostatic clips, and reliable closure methods need to be developed.

Figure 1.  Endoscopic and Laparoscopic view of the creation of the gastrotomy.


Figure 2.  Dissection of the triangle of Callot with flexible instruments.


Currently, transvaginal access is the preferred approach in humans because this route obviates the risk of intestinal content leakage via an imperfectly closed access site. Almost all reported procedures performed through natural orifices use some form of transparietal assistance. Anecdoctical hybrid NOTES appendectomies and cholecystectomies series have been reported by several surgical groups with good outcomes. Transparietal assistance for exposure of the gallbladder, application of laparoscopic clips to seal the cystic duct and assistance in visualization and dissection, is provided by needleport, laparoscopic trocars or transvaginal long grasping forceps(31–42) Figure 3. The time required to complete the procedure showed great variation (range, 35–210 min). The postoperative outcome is favourable in most of studies. Biliary leaks were reported in two studies, treated succesfully by endoscopic drainage and stenting(38,43). Few gynecological complications were reported. Clipping of the elements of the cystic pedicle is still an issue as there is no approved flexible endoscopic clip applier. However, to perform pure NOTES, some surgeons used endoclips or endoloops, or special long clip applier introduced trhough the vagina. No clinical randomized trial comparing NOTES and laparoscopic cholecystectomy has ever been published.

Figure 3.  Transvaginal cholecystectomy: laparoscopic view of the transvaginal endoscope and retraction grasper.


NOTES transgastric appendectomy was intially reported by Rao et al. (28) and was at the origin of the enthousiasm for this new surgical technique. Four other centers reported appendectomy performed through the vagina(35,44–46) or through the stomach(35). These are anecdodictal reports and no conclusion can be drawn. NOTES is apllied in its pure(28,44) or hybrid form (45–47). Transgastric drainage of a perigastric abcess and extraction of an infected gastric band was reported and demonstrated the promising convergence of intra and transluminal therapeutic endoscopy(48).

Reports of NOTES sleeve gastrectomy(49,50), splenectomy(51) and sigmoidectomy(52) must be considered as laparoscopic procedures assisted by transluminal endoscopy. Vision is provided by the flexible endoscope while the majority of the operative steps are performed with laparoscopic trocars and instruments.

Jump to…Top of pageAbstractIntroductionCurrent status of NOTESTechnological developmentThe Future of NOTESReferences 

Technological development

  1. Top of page
  2. Abstract
  3. Introduction
  4. Current status of NOTES
  5. Technological development
  6. The Future of NOTES
  7. References

The current flexible endoscope and flexible instrumentation poses several problems when used outside the confined environment of the lumen of organs. Endoscopes are too floppy, offering small instrument channels, small suction channel, insufflation noncontinuous and not pressure regulated.

Flexibility is necessary to introduce the endoscope through the natural orifices and navigate in the lumen of the organs. Flexibility becomes a problem when the endoscope is pushed outside the lumen of the organs into the peritoneal cavity. Orientation and stability are the preliminary requirements that will enable achievement of surgical procedures. When the target tissue is reached, retraction and dissection are virtually impossible because there is no current instrumentation that provides efficient grabbing and dissection capabilities and the instruments cannot offer triangulation at the tip of the endoscope. The efficacy of maintaining and monitoring pneumoperitoneum is a significant issue. On-demand insufflation with a standard endoscopic insufflator resulted in a marked increase and wide variation in intra-abdominal pressure throughout transgastric peritoneoscopy in an animal model(53).

Therefore, in addition to safe access and closure, it is necessary to develop a new platform for navigation and instrumentation. The general path is to transform an endoscopic concept, where the surgeon is driving simultaneously the optical system and the instruments, into a system where there the surgeon drive independently the instruments while another person guides the optical system. Larger, stronger, eventually articulated, instruments passed through large working channels are necessary. The concept has also to take into consideration the maximum size of the endoscope that will be accepted by the hollow viscus chosen to get access to the peritoneal cavity. The upper limit was fixed, without consultation between research and development teams, at 20 mm for a transgastric access. There are currently various operative platforms and instruments under investigation. The Endosurgical Operating System (EOS, USGI Medical, San Clemente, CA, USA) provides support to large instruments, without possibility of triangulation(54) The direct drive endoscopic system (DDES, Boston Scientific, Natick, MA, USA) is an ergonomic, table-mounted, operative platform providing 5 degrees of freedom to the tip of the instruments(55). Another prototype of operating endoscope is known as the “Anubiscope” (Karl Storz Endoskope, Tuttlingen, Germany) Figure 4 This unique four-way articulating flexible endoscope, with a built-in light and video source, has a 16 mm diameter insertion shaft with an 18mm diameter distal articulating vertebrae section and distal head. The distal head incorporates two opposing, movable arms with 4.2 mm working channels. External to these arms are jaws that function similar to a blunt tip trocar when in the closed position. In the open position, the jaws create triangulation of the working channels. A series of specialized hand instruments offer two-way articulation. The “Endo Samurai” (Olympus Medical, Tokyo, Japan) aims also at providing triangulation of the instruments, using a different operating mode.

Figure 4.  Anubiscope (Karl Storz, Tuttlingen, Germany).


A promising solution is the development of robotic endoscopic technology. Single robotisation of the driving wheels on a current endoscope is not helpful(56). An endoscopic robotic platform requires the development of a fully articulated device that can offer forward propulsion to the target tissue, with adequate triangulation of instruments at the tip.

A original robotic system was used with success in transgastric hepatic resections(57). The original feature of this system is the master control that uses movement sensors on the operator’s wrists and fingers and allows triangulation of instruments.

A more futuristic path of development is the use of a cluster of collaborative microrobots introduced in the peritoneal cavity through natural orifices. When they are positioned, the robots provide vision, retraction, and the adequate instrumentation to achieve surgical tasks. Experimentally, such a cluster of microrobots has been successfully used to perform a minimally invasive cholecystectomy.

Although of interest to gastroenterologists and GI surgeons, the future of NOTES lies not only in the development of adequate technologies but also in the patient’s perception of the potential advantages and risks of such an innovative approach. Both parameters are strongly linked, as there is no future for a technique that would be used in a minority of patients.

Cholecystecomy has become the most common NOTES procedure. Although NOTES is still evolving, studies demonstrate that a majority of patients perceive NOTES favorably as a potential technique for a cholecystectomy. This preference for NOTES diminished remarkably if the complication rates were greater than that for a laparoscopic cholecystectomy(60,61). Procedure-related risks, pain, and recovery time were more important than cosmesis, cost, length of hospital stay, and anesthesia type in the choice.

Cholecystectomy provides a model with which to evaluate NOTES. The excellent results of laparoscopic cholecystectomies have created the optimal benchmark. It is difficult to improve on laparoscopic procedures that deserve minimal morbidity despite several small incisions. The ideal application is yet to be found. Common procedures will be targeted for their potential high-volume application which appeals support of the industry. Addition of new diagnostic and therapeutic tools, such as virtual biopsy using confocall microscopy(62), lymph node mapping(63,64), may pave the way to further reduction in invasiveness of surgery.

source: Asian  journal of endoscopic surgery

New Discovery Points to How Dry Macular Degeneration Causes Blindness

A team of researchers, led by University of Kentucky ophthalmologist Dr. Jayakrishna Ambati, has discovered a molecular mechanism implicated in geographic atrophy, the major cause of untreatable blindness in the industrialized world. Their article, “DICER1 Deficit Induces Alu RNA Toxicity in Age-Related Macular Degeneration,” was published online by the journal Nature on February 6, 2011.

Concurrent with this discovery, Ambati’s laboratory developed two promising therapies for the prevention of the condition. This study also elaborates, for the first time, a disease-causing role for a large section of the human genome once regarded as non-coding “junk DNA.”

Geographic atrophy, a condition causing the death of cells in the retina, occurs in the later stages of the “dry type” of macular degeneration, a disease affecting some 10 million older Americans and causing blindness in over 1 million. There is currently no effective treatment for geographic atrophy, as its cause is unknown.

Ambati’s team discovered that an accumulation of a toxic type of RNA, called Alu RNA, causes retinal cells to die in patients with geographic atrophy. In a healthy eye, a “Dicer” enzyme degrades the Alu RNA particles.

“We discovered that in patients with geographic atrophy, there is a dramatic reduction of the Dicer enzyme in the retina,” said Ambati, professor and vice chair of the Department of Ophthalmology and Visual Sciences and the Dr. E. Vernon and Eloise C. Smith Endowed Chair in Macular Degeneration Research at the UK College of Medicine. “When the levels of Dicer decline, the control system is short-circuited and too much Alu RNA accumulates. This leads to death of the retina.”

Alu elements make up a surprisingly large portion—about 11 percent by weight—of the human genome, comprising more than 1 million sequences. However, their function has been unknown, so they have been called “junk” DNA or part of the “dark” genome. The discovery of Alu’s toxicity and its control by Dicer should prove of great interest to other researchers in the biological sciences, Ambati says.

Ambati’s team developed two potential therapies aimed at preventing geographic atrophy and demonstrated the efficacy of both approaches using laboratory models. The first involves increasing Dicer levels in the retina by “over-expressing” the enzyme. The second involves blocking Alu RNA using an “anti-sense” drug that binds and degrades this toxic substance. UK has filed patent applications for both technologies, and Ambati’s group is preparing to start clinical trials by the end of this year.

Response from the scientific community has been enthusiastic.

“These findings provide important new clues on the biological basis of geographic atrophy and may provide avenues for intervention through preventing toxic accumulation of abnormal RNA products,” said Dr. Paul Sieving, director of the National Eye Institute.

“Ambati’s latest research provides important mechanistic insights in geographic atrophy, and identification of this novel pathway may result in new therapeutic targets for a major cause of blindness,” said Dr. Napoleone Ferrara, a member of the National Academy of Sciences and Lasker-DeBakey awardee who is a researcher at Genentech.

This work has “widespread implications” for future study, said Dr. Stephen J. Ryan, president of the Doheny Eye Institute and member of the Institute of Medicine.

“The authors have opened an important line of research with real possibilities for future therapeutic intervention for patients with geographic atrophy,” Ryan said.

retinal-photographs.jpgsource: journal of macular degeneration

Spinal Cord Imaging in Patients with Radiologically Isolated Syndrome

Magnetic resonance imaging of the cervical spinal cord may help predict conversion to a clinically isolated syndrome.

Radiologically isolated syndrome (RIS) describes individuals with incidental findings highly suggestive of demyelinating lesions on magnetic resonance imaging (MRI) — i.e., periventricular, ovoid, juxtacortical, gadolinium-enhancing, or posterior fossa lesions (Neurology 2009; 72:800). Whether to treat such asymptomatic or “presymptomatic” individuals remains controversial.

To examine the predictive value of spinal cord lesions in patients with RIS, researchers identified 71 patients who had spinal cord imaging, out of 102 who had received a diagnosis of RIS after brain MRI for headaches, trauma, syncope, volunteering as a “healthy” control for research, or other reasons. Cervical cord was imaged in all 71 patients and thoracic cord in 17 of the 71. Spinal lesions had to be well circumscribed, distinct, and observed on more than one MRI sequence or plane.

Cervical cord abnormalities were present in 35% (25/71) of patients, with enhancement observed in 6 of those 25. The thoracic cord was abnormal in 6 of 17; 5 of those 6 had concomitant cervical lesions. Of the 25 patients with cervical lesions, 84% developed clinical progression to a clinically isolated syndrome (CIS; n=19) or primary progressive multiple sclerosis (n=2) within a median of 1.6 years (interquartile range, 0.8–3.8 years). Clinical progression occurred in only 3 of 46 patients without a cervical cord abnormality. The presence of a clear spinal cord lesion was associated with progression to a clinical event with 88% sensitivity, 92% specificity, and a positive predictive value of 84%.

Comment: These findings support obtaining a cervical spinal cord MRI scan for asymptomatic individuals whose brain MRI suggests demyelinating lesions. Thoracic cord imaging may not be necessary for all cases, as 83% of those with a thoracic lesion also had a cervical lesion. One study limitation is the small number of cases compared with modern CIS cohorts. Also, not all individuals with RIS underwent spinal cord imaging; although no differences were reported between those with and without cord imaging, a selection bias may still be possible. Confirmation of these findings in a separate, larger cohort would be helpful. For now, we can advise patients of the high sensitivity in predicting a clinical demyelinating event when a spinal cord lesion is found with an asymptomatic brain MRI scan compatible with demyelination. Although treatment of RIS will remain controversial, this study may help with a treatment decision in select cases.

Robert T. Naismith, MD

Published in Journal Watch Neurology February 8, 2011

New Anticoagulants for Venous Thromboembolism

Apixaban bested enoxaparin for VTE prophylaxis after hip replacement, and rivaroxaban outperformed standard therapy in patients with acute deep venous thrombosis.

Heparin, low-molecular-weight heparin (LMWH), and warfarin are the anticoagulants traditionally used for the prevention and treatment of venous thromboembolism (VTE). However, these agents require parenteral administration and frequent monitoring or have a narrow therapeutic index. Apixaban and rivaroxaban are new (and not yet FDA approved) anticoagulants that are given orally and do not require regular monitoring. Researchers tested these agents in separate industry-funded trials.

In the first trial — a multinational, double-blind study of VTE prophylaxis after hip replacement surgery — 5407 patients were randomized to receive oral apixaban (2.5 mg twice daily, initiated 12–24 hours after wound closure) or the LMWH enoxaparin (40 mg subcutaneously, 12 hours before surgery and then every 24 hours postoperatively) for 35 days. Major VTE, assessed using bilateral venography, occurred in 1.1% of apixaban recipients and 3.6% of enoxaparin recipients — a significant difference for both noninferiority and superiority. Apixaban had a similar advantage over enoxaparin for the primary composite endpoint of deep venous thrombosis (DVT), nonfatal pulmonary embolism, or death from any cause (1.4% vs. 3.9%). The two groups did not differ significantly in the composite incidence of major or clinically relevant nonmajor bleeding (roughly 5% in each group).

In the second trial — an open-label trial of therapy for acute, symptomatic proximal DVT — 3449 patients were randomized to receive either oral rivaroxaban (15 mg twice daily for 3 weeks and then 20 mg once daily) or subcutaneous enoxaparin followed by a coumarin. Treatment lasted for 3, 6, or 12 months. Recurrent VTE occurred in slightly fewer rivaroxaban than standard-therapy recipients (2.1% vs. 3.0%), and the bleeding rate was identical in the two groups (8.1%). Patients who completed 6 or 12 months of therapy were then randomized to receive rivaroxaban (20 mg once daily) or placebo for an additional 6 to 12 months. Recurrent VTE occurred in significantly fewer rivaroxaban recipients than placebo recipients (1.3% vs. 7.1%; P<0.001), but major bleeding occurred more often with rivaroxaban (4 episodes [0.7%], vs. none).

Comment: Apixaban and rivaroxaban specifically target factor Xa, which occupies a central position in the coagulation cascade. Although the agents were safe and effective in these two clinical trials, the comparisons with the older anticoagulants are open to question. In the prophylaxis study, enoxaparin was given in lower doses (40 mg daily) than those used in North America (30 mg twice daily). In the treatment trial’s extension phase, anticoagulants were stopped after 6 or 12 months in the placebo group, which might be premature for some patients (as suggested by the roughly 7% incidence of VTE). Rivaroxaban’s noninferiority and superiority to longer-term coumarin are unclear.

David Green, MD, PhD

Published in Journal Watch Oncology and Hematology February 8, 2011