REVIEWS Urological applications of natural orifice transluminal endoscopic surgery (NOTES) Mark D. Tyson and Mitchell R. Humphreys Abstract | Improvements in surgical techniques, and particularly the development and widespread clinical introduction of laparoscopy in the past two decades, have revolutionized the management of urological disease. Natural orifice transluminal endoscopic surgery (NOTES) holds promise in further advancing treatment outcomes in urology. This novel minimally invasive surgical approach can negate the requirement for skin incisions and, therefore, could potentially improve morbidity, convalescence, and cosmesis. After considerable preclinical development, the feasibility of ‘hybrid’ NOTES—involving concurrent laparoscopy —and ‘pure’ NOTES nephrectomy and prostatectomy procedures has now been successfully demonstrated in patients with urological conditions, whereas proof-of-concept studies of NOTES partial cystectomy have been performed in animal models. Whether such procedures offer therapeutic and safety benefits compared with traditional laparoscopic techniques remains unknown; indeed, concerns remain over the potential perioperative and postoperative adverse events associated with NOTES, such as incomplete closure of the entry-point incision, infection, and haemorrhage. In particular, however, the requirement for the development of specific rationally designed NOTES instrumentation as well as specially trained, highly skilled personnel to perform the surgery continues to restrict the utility of NOTES. Thus, considerable effort is now needed to shift the focus of research to refining NOTES methodologies to enable translation of these promising proof-of-principle studies into the clinic. Tyson, M. D. & Humphreys, M. R. Nat. Rev. Urol. advance online publication 13 May 2014; doi:10.1038/nrurol.2014.96

Introduction

Department of Urology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA (M.D.T., M.R.H.). Correspondence to: M.R.H. humphreys.mitchell@ mayo.edu

The adoption of laparoscopy in the 1990s ushered in a new era in the surgical management of urological disease. The well-documented benefits of conventional laparoscopy compared with open surgery 1 have increased impetus in further mitigating the morbidity associated with surgery by reducing or altogether eliminating the need for incisions in the skin. Natural orifice trans­luminal endoscopic surgery (NOTES) is one such approach that has been h­eralded as the next frontier in minimally invasive surgery. Indeed, NOTES has garnered considerable interest over the past decade by surgeons all over the world. Owing to the reduced use of skin incisions, NOTES platforms might offer additional advantages over conventional laparoscopy in terms of morbidity, convalescence, and cosmesis, including shorter recovery times, decreased pain, and reduced risks of adhesion, infection, and herni­ ation; however, the emergence of rigorous scientific evidence supporting this technique has been slow to coalesce. Furthermore, fundamental challenges to the adoption of NOTES in the clinical management of patients remain, particularly relating to the safety of viscerotomy, successful closure of the access point, and the development and implementation of specialized instrumentation. After extensive preclinical investigation of this methodology in various animal and cadaveric models, reports of the Competing interests The authors declare no competing interests.

clinical use of NOTES procedures in the urology setting are now emerging, and have demonstrated safe outcomes with a high degree of reproducibility. In this Review, we provide a focused summary of the relevant nomenclature and the history of NOTES techniques. In addition, we discuss the comparative outcomes research performed to date, and the current status of NOTES nephrectomy, prostatectomy, and cystectomy, including the barriers that continue to restrict the clinical adoption of these techniques. The future directions of this new f­rontier in the field of urological surgery are also considered.

NOTES nephrectomy

In 1869, Gustav Simon 2 cured a urinary fistula by success­fully performing the first planned nephrectomy (Figure 1 (Timeline)), although several inadvertent nephrectomies and partial nephrectomies had previously been performed during hepatobiliary and gynaecological explorations, with inauspicious outcomes. The next century witnessed considerable advancements in anaesthesia and open surgical techniques; however, laparoscopic nephrectomy was not described in the clinic until 1991, when Clayman and colleagues3 first performed this procedure to completely remove a tumour-bearing kidney from an 85-year-old woman. This feat ignited considerable interest in minimally invasive surgery, and especially in laparoscopic techniques, given the advantages such approaches hold over traditional open-surgery

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REVIEWS Key points ■■ Natural orifice transluminal endoscopic surgery (NOTES) nephrectomy, prostatectomy, and partial cystectomy are novel surgical techniques with tremendous promise as innovative approaches to the treatment urological diseases ■■ NOTES techniques have undergone extensive preclinical development over the past decade, which has increased understanding and led to refinement of the methodology ■■ NOTES can be performed via transgastric, transurethral, transrectal, and transvaginal routes, and either alone as ‘pure NOTES’, or in combination with laparoscopy surgery as ‘hybrid NOTES’ ■■ In humans, NOTES procedures have primarily been used in proof-of-principle studies in cadavers or select patients; however, these have proven the feasibility of NOTES nephrectomy and prostatectomy ■■ Considerable challenges continue to limit the widespread adoption of NOTES, including potential safety concerns, an unmet need for dedicated, specifically designed instruments, and the shortage of suitably skilled surgeons ■■ Furthermore, stringent validation and comparison with laparoscopy and opensurgery techniques is needed to ensure that the current enthusiasm for NOTES techniques is supported by measureable improvements in patient outcomes

procedures, such as minimal scarring, decreased pain, and shorter convalescence.2 With an emphasis on these outcomes, NOTES is now being studied as a potentially even less invasive alternative to conventional laparoscopy.

Preclinical development of NOTES nephrectomy Prior to the introduction of NOTES nephrectomy into the clinical setting, this surgical technique underwent several iterations in preclinical animal models. Gettman et al.4 published a seminal NOTES study in 2002, which actually predated the coining of the ‘NOTES’ acronym, after performing six transvaginal laparoscopic nephrectomies in a pig model (Figure 1 (Timeline)); a ‘hybrid’ NOTES technique involving a concurrent trans­abdominal laparo­ scopic port was used in five of these nephrectomies, whereas one ‘pure’ NOTES nephrectomy, in which no external incision was made, was conducted.4 The operative time in the pure NOTES nephrectomy was 360 min, compared with a mean operative time of 210 min in the five hybrid procedures.4 Notably, one of the pigs exsangui­ nated owing to intraoperative injury to the renal hilar structures caused during placement of the endovascular stapler,4 which underscored the need for specialized instrumentation before exposing patients to the techniques used. After this initial report, a series of proofof-principle animal and cadaveric studies continued to refine the surgical techniques for NOTES nephrectomy (Table 1).5–22 One of the main limitations in performing NOTES nephrectomy highlighted by Gettman et al.4 was the cumbersome nature of the standard laparoscopic instruments. The available instruments did not enable robust retraction of the retroperitoneal tissue, or the ability to perform controlled blunt dissection that is vital to the dissection of the renal unit—especially in humans, as humans have substantially more peri­nephric fat than pigs. Furthermore, the available instruments were inserted parallel to the endoscope, which limited the ability of the surgeon to triangulate tissue for efficient traction and counter traction, and also simultaneously

limited visibility along the working access. As such, the successful clinical implementation of these techniques became dependent on the innovative solutions of early surgical pioneers to overcome the limitations imposed by conventional laparoscopic instrumentation. To address some of the technical challenges facing NOTES nephrectomy, several methodological adaptations were subsequently explored. Multitasking platforms, such as the TransPort™ multilumen operating platform (USGI Medical, USA), were identified as tools that could facilitate NOTES.6,7 The novelty of the TransPort™ multilumen device, in particular, was that it remained flexible during insertion, but could be locked in place to create a rigid platform from which to visualize and perform multiple complex surgical procedures via four integrated largediameter access channels.6,7 In addition, Zeltser et al.23 developed a magnetically anchored guidance system, which they used to perform a laparoscopic nephrectomy with instruments inserted via a single transabdominal port in a pig model (Figure 1 (Timeline)). Zeltser and colleagues23 concluded that this guidance system enabled unhindered intracorporeal manipulation of instruments and might be a­menable to external incision-free NOTES. Robotic platforms represent another logical avenue of exploration in NOTES, especially given the relative familiarity of the da Vinci®surgical systems (Intuitive Surgical, USA) among operating teams after the widespread adoption of robot-assisted surgery in urology. Robots hold additional promise in improving visualization and in articulating laparoscopic instruments that are particularly well suited to suturing and knot tying. However, initially attempts to incorporate conventional robotic platforms into NOTES procedures performed in pigs were affected by substantial extracorporeal clashing of the arms of the robots, owing to the extreme proximity of the robotic ports during such procedures.7 Furthermore, only the da Vinci® S and Si systems were adaptable for robot-assisted NOTES, given the longer instruments and improved ranged of motion of these devices compared with the standard da Vinci model®.7

Entry of hybrid NOTES in the clinical setting The pure NOTES nephrectomy methodologies that have been used in patients evolved through a stepwise technological progression via various forms of hybrid NOTES procedures. For example, the vagina gained acceptance as a viable extraction portal in women after laparoscopic nephrectomy over two decades ago,24,25 but the concept of a transvaginal nephrectomy did not materialize until 2008 when Branco et al.26 first demonstrated that the vagina could also be used as a working port in a 23 year old woman with recurrent UTIs and a nonfunctioning kidney (Figure 1 (Timeline)). Branco and co-workers26 used a hybrid NOTES technique involving two additional 5 mm laparoscopic ports, a double-channel flexible endoscope, and a polypectomy snare to complete the procedure. Operative time was 170 min, estimated blood loss was only 350 ml, no operative complications occurred, and the patient recovered uneventfully within a 12‑h hospitalization period.26

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REVIEWS Timeline | Key milestones in the development of NOTES Gustav Simon2 successfully performs the first planned nephrectomy for urinary fistula

Branco and co-workers26 perform the first transvaginal hybrid NOTES nephrectomy, involving two laparoscopic ports, in a 23-year-old woman with a nonfunctioning kidney

Gettman and co-workers4 perform one pure NOTES and five hybrid transvaginal NOTES/laparoscopy nephrectomies in pigs

1869

1991

2002

Zeltser et al.23 developed a magnetically anchored guidance system, amenable to hybrid NOTES nephrectomy, that enables laparoscopic nephrectomy using a single transabdominal port in a pig model

First laparoscopic nephrectomy performed by Clayman and colleagues3

Humphreys et al.39 and Nagele and co-workers40 perform NOTES radical prostatectomy in men with prostate cancer

First HoLEP-based NOTES radical prostatectomies performed by Humphreys and colleagues37 in cadavers

2007

Laydner et al.35 show that a novel prone jackknife retroperitoneal approach to robot-assisted transvaginal pure NOTES nephrectomy is feasible in cadavers

Krambeck et al.38 demonstrate the feasibility of NOTES radical prostatectomy in a live animal model (dogs)

2008

Alcaraz et al.31 demonstrate the feasibility of transvaginal hybrid NOTES in live-donor nephrectomy

2009

2010

2011

2012

Kaouk et al.28 reduce the number of laparoscopic ports used in clinical transvaginal hybrid NOTES nephrectomy from two to one

Kaouk et al.33 report the first pure transvaginal NOTES nephrectomy in a 58-year-old woman with an atrophic kidney; no perioperative complications were reported, but the process was time consuming and technically difficult

Swayer et al.42 perform first transgastric and transurethral NOTES partial cystectomy in pigs

Hagen and co-workers34 find that transvaginal pure NOTES in cadavers in the lithotomy position is incompatible with the da Vinci® robotic platform

2013

Kaouk and colleagues32 perform robot-assisted transvaginal hybrid NOTES live-donor nephrectomy

Important events in the history of surgery that have advanced the management of urological disease and facilitated the ongoing development of NOTES procedures for nephrectomy, prostatectomy, and cystectomy. Abbreviations: HoLEP, holmium laser enucleation of the prostate; NOTES, natural orifice transluminal endoscopic surgery.

Subsequent to this initial report, hybrid NOTES neph­ rectomy underwent further technical modifications, and the indications in which this approach was used were expanded (Table 2): Alcaraz et al.27 demonstrated the feasibility of hybrid NOTES nephrectomy in the treatment of patients with kidney cancer; Kaouk et al.28 reduced the number of ports necessary for retraction of the mobilized kidney from two to one (Figure 1 (Timeline)); Porpiglia et al.29 reduced the size of the laparoscopic ports to 3.5 mm; Sotelo et al.30 utilized the transvaginal port to perform the majority of the intraoperative dissection; and Alcarez et al.31 and Kaouk et al.32 demonstrated the safety of NOTES-assisted living-donor nephrectomy. Indeed, transvaginal hybrid NOTES living-donor nephrectomy was reported to have no adverse effects on graft functioning in the recipient or the sexual activity of the donor.31 However, these reports highlighted some important perioperative challenges, including rectal injury caused during vaginal entry of the trocar, failure to progress with the dissection, intraoperative haemorrhage, and readmission for pelvic abscess drainage.27–32 Furthermore, notwithstanding the fact that these refinements in surgical methods represented important steps in the development of the pure NOTES technique, the holy grail of external-incision-less surgery had not been realized in these studies.

Pure NOTES nephrectomy in the clinic In 2010, Kaouk and colleagues33 at the Cleveland Clinic, OH, USA, reported the first pure transvaginal NOTES nephrectomy in a 58 year old woman with an atrophic right kidney (Figure 1 (Timeline)). Pneumoperitoneum was obtained via introduction of a blunt tip trocar into the peritoneal cavity through the vagina.33 Two standard 10 mm trocars and a 5 mm trocar were placed through

a GelPort® (Applied Medical, USA) in the 30 mm posterior colpotomy using a 5 mm deflecting laparoscope.33 A standard endovascular stapler was used to ligate the renal hilar structures, and the remaining upper pole and posterior attachments of the kidney were dissected using a monopolar J‑hook.33 Although no perioperative compli­cations were noted, the authors concluded that the procedure was tedious, time consuming (taking 420 min), and technically demanding.33 For these reasons, hybrid NOTES is often performed in lieu of pure NOTES, and several additional modifications to the hybrid NOTES technique have ensued.

Robot-assisted NOTES nephrectomy The incorporation of robotic technology has assisted some surgeons in overcoming some of the limitations in NOTES nephrectomy pertaining to instrumentation, including lack tissue triangulation, difficulty orientating apparatus, and overly flexible NOTES instruments. Hagen et al.34 attempted transvaginal pure NOTES with intersecting robotic instruments in a cadaver placed in the lithotomy position (Figure 1 (Timeline)); however, the lithotomy position was found to be incompatible with the da Vinci®robotic platform due to the clashing of the robotic arms. In response, Laydner et al.35 reported the feasibility of a robot-assisted transvaginal pure NOTES technique using a novel prone jackknife retro­peritoneal approach, which avoided clashing of the robotic arms during surgery in a cadaver study. Although many of these techniques are starting to be established in the field of urology, many challenges persist and continue to limit widespread clinical integration of NOTES. Nevertheless, this pioneering work in nephrectomy laid the groundwork for the application of NOTES techniques to other u­rological procedures, such as radical prostatectomy.

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REVIEWS Table 1 | Preclinical studies of NOTES nephrectomy Study

Surgery performed

Model

Approach used

Comments

Gettman et al. (2002)

6 nephrectomies

Pig

1 pure transvaginal and 5 hybrid transvaginal with additional transabdominal port for laparoscope

One pig exsanguinated, 2 required episiotomy, 1 had posterior vaginal wall laceration

Lima et al. (2007)5

6 nephrectomies

Pig

Combined transgastric and transvesical

Mild haemorrhage that was adequately controlled

Clayman et al. (2007)6

1 nephrectomy

Pig

Transvaginal with a single 12 mm trocar

No surgical complications

Box et al. (2008)7

1 nephrectomy

Pig

Transvaginal and transcolonic with single transabdominal port

First description of robot-assisted hybrid NOTES

Haber et al. (2008)8

10 pyeloplasties, 10 partial nephrectomies, and 10 radical nephrectomies

Pig

Transvaginal with single transabdominal port

Robot-assisted procedure improved intracorporeal suturing

Isariyawongse et al. (2008)9

Bilateral nephrectomy

Pig

Simultaneous transvaginal and transgastric pure NOTES

Standard laparoscopic instruments used with no complications

Crouzet et al. (2008)10

4 renal cryoablations

Pig

Transvaginal and transgastric pure NOTES

First reported use of NOTES cryoablation; no complications were observed

Haber et al. (2009)11

5 nephrectomies

Pig

Transgastric and transvaginal pure NOTES

No complications observed

Raman et al. (2009)

2 nephrectomies

Pig

Transvaginal pure NOTES

Used magnetically anchored guidance system

Perretta et al. (2009)13

12 nephrectomies

Pig and cadaveric

Transvaginal pure NOTES

Retroperitoneal approach was used in the porcine model, but was not reproducible in cadavers owing to tissue rigidity

Aron et al. (2009)14

4 nephrectomies

Cadaveric

Transvaginal with transabdominal port

1 aborted due to dense adhesions

Boylu et al. (2010)

1 partial nephrectomy

Pig

Transgastric with transabdominal laparoscope

Thulium laser was used for resection

Bazzi et al. (2011)16

3 nephrectomies

Pig

Transrectal with one transabdominal port

First report detailing transrectal NOTES

Baldwin et al. (2011)17

3 nephrectomies

Pig

Transureteral with 3 transabdominal ports

First transureteral NOTES nephrectomy

Sánchez-Margallo et al. (2012)18

10 nephrectomies

Sheep

Transvaginal with 2 transabdominal ports

No complications observed

Lima et al. (2012)19

6 nephrectomies

Pig

Transvesical

Morcellation of kidney tissue was performed in situ

Bazzi et al. (2012)20

4 nephrectomies

Cadaveric

Transrectal and one transabdominal port

Intact specimen extraction was reported

Bazzi et al. (2013)21

10 nephrectomies

Pig

5 transrectal, 5 transvaginal hybrid NOTES

Comparable perioperative parameters were observed using either approach

Eyraud et al. (2013)22

1 nephrectomy and adrenalectomy

Cadaveric

Transrectal hybrid NOTES

Robot-assisted procedure was used

Laydner et al. (2013)35

2 nephrectomies

Cadaveric

Transvaginal pure NOTES

Robot-assisted retroperitoneal approach with cadaver in prone jackknife position used to avoid clashing of the robot arms

4

12

15

Abbreviation: NOTES, natural orifice transluminal endoscopic surgery.

NOTES radical prostatectomy

Large, obstructing prostates, once managed using open prostatectomy, are now routinely managed endoscopically in patients with benign prostatic disease through holmium laser enucleation of the prostate (HoLEP). The current iteration of NOTES radical prostatectomy (NOTES RP) is an extension of HoLEP (Figure 2); thus, urologists with HoLEP experience are uniquely equipped with many of the skills required for NOTES RP. The unique properties of the holmium laser make it ideal for NOTES. For example, the 2140 nm wavelength energy produced by the holmium laser is absorbed by water and only penetrates tissues to a depth of around 0.4 mm,36 which enables highly effective haemostasis and precise dissection. However, before NOTES RP could be implemented in patients in the clinic, extensive preclinical animal and cadaveric development of the technique was required.

Preclinical studies of NOTES prostatectomy The first NOTES RP surgeries were performed by Humphreys et al.37 in four cadavers (Figure 1 (Timeline)); the surgeries were conducted by experienced teams at two different institutions that perform a high volume of HoLEP procedures.37 The technical apparatus used to carry out pure NOTES in this study included a 100 W holmium:yttrium–aluminium–garnet (Ho:YAG) laser (Versapulse®; Lumenis Surgical, USA), a 550 μm endfiring quartz laser fibre (SlimLine™ Reusable; Lumenis Surgical, USA), a 26F continuous-flow resectoscope with a laser bridge and a 7F laser stabilizing catheter (Cook Medical, USA).37 Resection of the prostate gland was performed entirely using the laser, and dissected prostate tissues were pushed into the bladder.37 A rigid, offset 27F nephroscope with a 5 mm working channel (Olympus, Japan) inserted via the outer resectoscope

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REVIEWS Table 2 | Clinical studies of NOTES procedures in urology Study

Surgery performed

Approach used

Complications

Comments

Branco et al. (2008)26

1 nephrectomy

Transvaginal hybrid NOTES

None

First report of hybrid NOTES nephrectomy performed in humans

Kaouk et al. (2009)28

1 nephrectomy

Transvaginal hybrid NOTES

None

Dense adhesions required use of an umbilical port

Sotelo et al. (2010)30

4 nephrectomies

Transvaginal hybrid NOTES

Rectal injury, failure to progress with dissection, and bleeding with readmission for abscess requiring drainage each observed in one patient

Only one umbilical trocar was used in each patient

Alcaraz et al. (2010)27

4 nephrectomies

Transvaginal hybrid NOTES

1 colonic injury

Two transabdominal trocars used

Kaouk et al. (2010)33

1 nephrectomy

Pure NOTES

None

3 cm colpotomy used

Alcaraz et al. (2011)31

20 donor nephrectomies

Hybrid NOTES

Acute haemorrhage in one donor

In comparison with matched laparoscopic donors, warm ischaemia time was increased in the NOTES group

Humphreys et al. (2011)39

2 radical prostatectomies

Pure NOTES with extraction incision

None within 30 days of NOTES

Suprapubic incision was used to extract tissue to check surgical margins

Kaouk et al. (2012)32

1 donor nephrectomy

Robot-assisted transvaginal hybrid NOTES

None

First robot-assisted hybrid NOTES donor nephrectomy

Abbreviation: NOTES, natural orifice transluminal endoscopic surgery.

sheath was used to perform vesicourethral anasto­mosis using a laparoscopic suture device and knot pusher in an interrupted fashion.37 The nephroscope also enabled endoscopic removal of prostate tissue within the bladder using a tissue morcellator (Versacut™, Lumenis Scientific, USA).37 Continuous normal saline irrigation via both the outer resectoscope sheath and the nephroscope was used to ensure the bladder was distended and, therefore, prevent damage to the bladder wall that can occur if the bladder collapses.37 After the initial NOTES RP pro­cedures were completed, the prostatic fossa was explored transabdominally to perform biopsies of the neuro­vascular bundles, bladder, and u­rethral margins, with analysis of the biopsy tissues demonstrating complete removal of all prostate tissue, with preservation of the neurovascular bundles bilaterally and the external urinary sphincter. Although many questions remained regarding the oncological efficacy of this technique (that is, whether all of the tumour can be removed), this initial proof-of-concept study demon­strated the feasibility of NOTES RP in a cadaveric model and provided a f­ramework for future study in animal models. The first animal study of NOTES RP was performed by Krambeck et al. 38 in six nonsurvival male dogs weighing between 50–70 lb (22.67–31.75 kg). Using a procedure similar to that used in the cadaveric study by Humphreys and colleagues,37 NOTES RP was successfully completed in all six animals (Figure 1 (Timeline)).38 However, substantial technical difficulties related to the intra-­abdominal location of the prostate in dogs complicated the completion of the vesicourethral anastomosis, secondary to fluid accumulation and anatomical constraints.38 In fact, successful vesicourethral anastomosis was completed in only one animal, and required the placement of vest sutures.38 Despite this problem, the

study demonstrated that NOTES RP could be completed with minimal bleeding and few adverse physiological effects, and the experience gained was used to guide the subsequent development and revision of specialized anastomotic equipment for NOTES RP. This investigation was also important in illustrating that concerns regarding the successful completion of this t­echnique, although c­onsiderable, were not insurmountable.

NOTES prostatectomy in the clinic In 2011, the first clinical experiences of NOTES RP were reported by both Humphreys et al.39 and Nagele et al. (Figure 1 (Timeline)).40 Humphreys and colleagues39 performed NOTES RP in two highly selected patients with low-grade, clinically localized prostate cancer. Similar instrumentation to that described in the cadaveric study 37 by the same group was used, with exception of the anastomotic equipment; instead of the laparoscopic suture device with knot pusher, a prototype cannula scope in conjunction with a prototype vesicourethral suturing device and a titanium knot applier was used to place six interrupted sutures,39 an approach that was first developed and demonstrated in a cadaveric model (M. R. Humphreys, unpublished work). Intraoperative cystograms demonstrated watertight anastomoses were achieved in both patients, and both individuals tolerated the procedure well without any perioperative complications.39 Pathological examination of the resected prostate tissue revealed that one patient had Gleason score 3 + 3, pT2a disease and the other had Gleason score 3 + 4, pT2c disease, with negative margins in both.39 To enable accurate pathological analysis of tumour, a suprapubic cystotomy extraction incision was required to remove the tissue en bloc.39 One patient experienced left-sided gluteal and suprapubic pain postoperatively, which

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REVIEWS a

b Prostate Oesophagus Stomach Endoscope

Liver

Liver

Bladder Kidney Kidney Stomach Endoscope

c

Endoscope

Colon

d

Endoscope Vagina

Bladder Uterus

Figure 2 | Approaches used in NOTES procedures. a | Transgastric approach to NOTES nephrectomy, which endoscopic access to the kidney achieved via the stomach. b | Demonstration of transrectal access to the kidney for NOTES nephrectomy, in which the instruments at progressed through the wall of the colon. c | Illustration of the tranurethral NOTES radical prostatectomy approach. d | Schematic representation of the route used to perform transvaginal NOTES nephrectomy. Abbreviation: NOTES, natural orifice transluminal endoscopic surgery.

resolved without intervention, and 30-day outcomes were notable for unremark­able convalescence, with only one patient wearing security pads for continence issues.39 In the study by Nagele and co-workers,40 NOTES RP was performed in a man aged 77 years with localized bilateral prostate cancer (Gleason 3 + 4 in 80% of 12 biopsy cores and a serum PSA concentration of 2.1 ng/ml) using a thulium laser. The thulium laser differs from the holmium laser in that the wavelength of light emitted is even closer to the peak absorption of water, making absorption by tissue even more efficient, theoretically.41 The tumour tissue was retrieved by cystolitho­tomy, involving an incision in the lower abdomen, and the overall operating time was 312 min.40 No postoperative complications were noted and a cysto­gram performed at 7 days after surgery showed no signs of urinary extra­ vasation.40 The authors of this study concluded that this NOTES RP approach was safe and feasible.40 Although the long-term oncological and functional outcomes remain unpublished, these studies demon­strated the clinical feasibility of NOTES RP and that this approach might represent a future treatment option for selected patients with low-risk prostate cancer.

NOTES cystectomy

At present, data on NOTES cystectomy are limited to one published report. Swayer et al.42 described two pure NOTES techniques for partial cystectomy (transurethral and transgastric) in a pig model (Figure 1 (Timeline)). The first technique was a transurethral pure NOTES partial cystectomy approach, with no intra-abdominal ports, that was successful in both nonsurvival (n = 2) and survival (n = 2) models, whereas the second method was an extravesical transgastric pure NOTES technique with cystoscopic guidance that was successfully performed in a single nonsurvival animal.42 For both approaches, endoscopic loop devices were used to isolate the desired area of the bladder before resection, and to close the defect, with subsequent reinforcement by endoscopically delivered clips. Swayer et al.42 concluded that the transurethral NOTES method might be the least invasive approach to partial cystectomy, but the transgastric technique has advantages relating to visualization of adjacent structures, accessibility to certain anatomical sites, and lymph node sampling; however, transgastric NOTES might be associated with greater morbidity. No cadaveric or clinical studies of NOTES cystectomy have been performed to

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REVIEWS date. Nevertheless, this methodology holds promise as a less-invasive alternative to conventional partial cystectomy techniques, and therefore might reduce the m­orbidity associated with such procedures.

Barriers to the adoption of NOTES

Whether NOTES techniques will actually deliver clear advantages over conventional laparoscopy in terms of morbidity and patient recovery remains to be discerned. Theoretical benefits of NOTES, owing to the reduced reliance on skin incisions, include improved cosmesis, shortened convalescence times, reduced pain,43 decreased wound infections,44,45 and a reduction in herniation and adhesions;44,45 however, these potential benefits might be offset by complications related to the point of access. Although the vagina seems to be an ideal portal of entry for NOTES nephrectomy compared with other points of access, given that no gastrotomy is required, several reports have indicated that considerable morbidity can nonetheless accompany this approach, not to mention the obvious limitation of gender confinement. In one case series of 102 transvaginal NOTES procedures, 46 three major complications occurred, specifically rectal injury, omental bleeding, and abscess formation. In addition, seven minor complications were noted and included dislodgement of an intrauterine device and formation of vaginal granulation tissue.46 In a separate international multicentre NOTES registry,47 an overall complication rate of 6.9% was reported for the transvaginal approach. Although these rates of complications associated with transvaginal NOTES are low, the occurrence of the adverse events, with the exception of abscess formation, in patients treated using conventional laparoscopic approaches is generally lower. Taken together, these data suggest that transvaginal NOTES techniques are still very much in their infancy and will require further modifications before they are ready for widespread integration in the clinic. Another important impediment to the clinical implementation of NOTES pertains to the lack of adequate instrumentation. Several of the reported NOTES pro­ cedures indicated that standard laparoscopy instruments were used, which probably have intrinsic ergonomical limi­tations and thus present technical difficulties that might compromise patient safety (lack of triangulation and difficult orientation of apparatus, for example). Furthermore, sufficient transmission of force via the flexible instruments used for tissue dissection and retraction might increase the complexity of NOTES. Before NOTES techniques solidify their place in the surgical armamentarium of urologists, rationally designed, specially made instruments that address these limitations and are specific to these methodologies need to be fashioned. The production of such instruments will undoubtedly rely on successful collaborations between urologists and engineers with a vision for clinical translational of this approach. Several other limitations to NOTES are important to appreciate. First, the importance of the reliable closure of the point of access cannot be overstated. Experts agree that even low rates of leakage from the luminal access point would be unacceptable given the safety of other

minimally invasive alternatives to NOTES procedures.48 Second, prevention of infection is an increasing concern, especially with transrectal and transvaginal approaches to NOTES (Figure 2). Even the use of transgastric points of access to the peritoneal cavity might increase the risk of intra­peritoneal contamination with pathogens. In many instances, preoperative antibiotics is likely to be sufficient for prophylaxis of infection that might occur after surgery, but this issue will undoubtedly require further study in patients. Third, the management of peri­operative complications and intraoperative haemorrhage could potentially pose added challenges for NOTES platforms. Although many of these operative complications will probably be similar to those that surgeons have managed in laparoscopic and open surgery, novel complications that are unique to NOTES might also become evident. Finally, the funda­mental skillsets required to perform many NOTES pro­cedures will require that surgeons have extensive training in both laparoscopy and endoscopy. Urologists are uniquely skilled in both of these domains, but individ­uals interested in performing such techniques will need ample training at a facility with good animal resources and appropriate equipment, at least in the short term. Poor outcomes by surgeons taking cavalier forays into the realms of NOTES without adequate experience might lead to unaccept­ably high complication rates and precipitate regulatory intervention, which could have the un­toward con­sequence of preventing the advancement of the methodology in the clinical arena. Indeed, as techniques that are proven to be reproducibly safe and efficacious in patients are developed, guidelines for training that enables other individuals to safely and success­fully perform the procedures need to be implemented by the key stakeholder organizations.

The future of NOTES techniques

For NOTES to continue to mature into a clinically viable treatment option, that both procedure and device develop­ ment must continue is clear. However, at present, the focus of NOTES research should begin to transition from feasibility and proof-of-principle studies to the improvement and refinement of these techniques, with the ultimate goal of proceeding with comparative studies—at least with regard to NOTES nephrectomy. Although NOTES techniques are currently in vogue among highly skilled laparoscopists, we must balance such enthusiasm for this approach with a degree of healthy scientific scepticism. To our knowledge, limited head-to-head data comparing NOTES techniques with conventional laparoscopy procedures is available. Such comparative studies would be fraught with statistical bias, nevertheless, they are a necessary first step to test the hypothesis that NOTES techniques are at least as safe as laparoscopy in selected populations. From this foundation, efforts can build towards achieving the ambitious goal of proceeding with randomized clinical trials; this goal is unlikely to be reached, but one could argue that evidence from such studies that demonstrate the superiority of many laparoscopic and/or robotic surgical methods also remain absent. In the meantime, focusing on the improvement of instrumentation, consolidation

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REVIEWS of the best surgical methods with the safest points of access, and identifying potential areas of improvement regarding patient outcomes will be vital to the growth and s­ustainability of NOTES methods in the long term.

Conclusions

Review criteria

NOTES nephrectomy, prostatectomy, and partial cystectomy are novel techniques that hold incredible potential as innovative treatment approaches for urological diseases. Equally, however, future integration of these approaches into the clinical landscape faces considerable challenges. Although early pioneers of NOTES have contributed considerable time, resources, and skill to overcome many of these challenges, further progress will unquestionably rely on the innovative contributions by future investigators. Furthermore, NOTES will have to undergo stringent validation in comparison with laparo­scopy and open 1.

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surgical techniques to ensure that the enthusiasm for this potentially less-invasive therapeutic approach is matched by measureable improvements in patient outcomes.

A comprehensive literature search was conducted focusing on NOTES procedures in urology. The articles discussed in this Review were identified in the MEDLINE database using the following MeSH terms for English-language articles: “natural orifice transluminal endoscopic surgery”; “NOTES”; “NOTES nephrectomy”; “NOTES prostatectomy”; “NOTES cystectomy”; “NOTES outcomes”; “NOTES porcine”; “hybrid NOTES”; and “pure NOTES”. All articles published before completion of this search in January 2013 were eligible for inclusion. The reference list of the publications identified were also searched for other relevant articles for inclusion.

15. Boylu, U., Oommen, M., Joshi, V., Thomas, R. & Lee, B. R. Natural orifice translumenal endoscopic surgery (NOTES) partial nephrectomy in a porcine model. Surg. Endosc. 24, 485–489 (2010). 16. Bazzi, W. M. et al. Transrectal hybrid natural orifice transluminal endoscopic surgery (NOTES) nephrectomy in a porcine model. Urology 77, 518–523 (2011). 17. Baldwin, D. D. et al. Hybrid transureteral natural orifice translumenal endoscopic nephrectomy: a feasibility study in the porcine model. J. Endourol. 25, 245–250 (2011). 18. Sánchez-Margallo, F. M. et al. Transvaginal NOTES-assisted laparoscopic nephrectomy: a survival study in a sheep model. Surg. Endosc. 26, 926–932 (2012). 19. Lima, E., Branco, F., Parente, J., Autorino, R. & Correia-Pinto, J. Transvesical natural orifice transluminal endoscopic surgery (NOTES) nephrectomy with kidney morcellation: a proof of concept study. BJU Int. 109, 1533–1537 (2012). 20. Bazzi, W. M. et al. Feasibility of transrectal hybrid natural orifice transluminal endoscopic surgery (NOTES) nephrectomy in the cadaveric model. Urology 80, 590–595 (2012). 21. Bazzi, W. M. et al. Comparison of transrectal and transvaginal hybrid natural orifice transluminal endoscopic surgery partial nephrectomy in the porcine model. Urology 82, 84–89 (2013). 22. Eyraud, R. et al. Robot-assisted transrectal hybrid natural orifice translumenal endoscopic surgery nephrectomy and adrenalectomy: initial investigation in a cadaver model. Urology 81, 1090–1094 (2013). 23. Zeltser, I. S. et al. Single trocar laparoscopic nephrectomy using magnetic anchoring and guidance system in the porcine model. J. Urol. 178, 288–291 (2007). 24. Breda, G. et al. Laparoscopic nephrectomy with vaginal delivery of the intact kidney. Eur. Urol. 24, 116–117 (1993). 25. Gill, I. S. et al. Vaginal extraction of the intact specimen following laparoscopic radical nephrectomy. J. Urol. 167, 238–241 (2002). 26. Branco, A. W. et al. Hybrid transvaginal nephrectomy. Eur. Urol. 53, 1290–1294 (2008). 27. Alcaraz, A. et al. Feasibility of transvaginal NOTES-assisted laparoscopic nephrectomy. Eur. Urol. 57, 233–237 (2010).

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28. Kaouk, J. H. et al. NOTES transvaginal nephrectomy: first human experience. Urology 74, 5–8 (2009). 29. Porpiglia, F., Fiori, C., Morra, I. & Scarpa, R. M. Transvaginal natural orifice transluminal endoscopic surgery-assisted minilaparoscopic nephrectomy: a step towards scarless surgery. Eur. Urol. 60, 862–866 (2011). 30. Sotelo, R. et al. NOTES hybrid transvaginal radical nephrectomy for tumor: stepwise progression toward a first successful clinical case. Eur. Urol. 57, 138–144 (2010). 31. Alcaraz, A. et al. Feasibility of transvaginal natural orifice transluminal endoscopic surgeryassisted living donor nephrectomy: is kidney vaginal delivery the approach of the future? Eur. Urol. 59, 1019–1025 (2011). 32. Kaouk, J. H. et al. Transvaginal hybrid natural orifice transluminal surgery robotic donor nephrectomy: first clinical application. Urology 80, 1171–1175 (2012). 33. Kaouk, J. H. et al. Pure natural orifice transluminal endoscopic surgery (NOTES) transvaginal nephrectomy. Eur. Urol. 57, 723–726 (2010). 34. Hagen, M. E. et al. Robotic single-incision transabdominal and transvaginal surgery: initial experience with intersecting robotic arms. Int. J. Med. Robot. 6, 251–255 (2010). 35. Laydner, H. et al. Robotic retroperitoneal transvaginal natural orifice translumenal endoscopic surgery (NOTES) nephrectomy: feasibility study in a cadaver model. Urology 81, 1232–1237 (2013). 36. Lerner, L. B. & Tyson, M. D. Holmium laser applications of the prostate. Urol. Clin. North Am. 36, 485–495 (2009). 37. Humphreys, M. R., Krambeck, A. E., Andrews, P. E., Castle, E. P. & Lingeman, J. E. Natural orifice translumenal endoscopic surgical radical prostatectomy: proof of concept. J. Endourol. 23, 669–675 (2009). 38. Krambeck, A. E., Humphreys, M. R., Andrews, P. E. & Lingeman, J. E. Natural orifice translumenal endoscopic surgery: radical prostatectomy in the canine model. J. Endourol. 24, 1493–1496 (2010). 39. Humphreys, M. R. et al. Natural orifice transluminal endoscopic radical prostatectomy: initial perioperative and pathologic results. Urology 78, 1211–1217 (2011). 40. Nagele, U. et al. Natural orifice (NOTES) transurethral sutureless radical prostatectomy with thulium laser support: first patient report. World J. Urol. 30, 625–631 (2012).

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—NOTES IMTN study: preliminary results of 362 patients. Surg. Innov. 17, 142–158 (2010). 48. Rattner, D., Kalloo, A. & ASGE/SAGES Working Group. ASGE/SAGES Working Group on Natural Orifice Translumenal Endoscopic Surgery. October 2005. Surg. Endosc. 20, 329–333 (2006). Author contributions M.D.T. researched the data for the article and M.R.H. reviewed/edited the manuscript before submission. Both authors substantially contributed to discussion of the content and writing the article.

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