Development and prospects of natural orifice specimen extraction surgery for colorectal cancer: a review article

Abstract

The natural orifice specimen extraction surgery (NOSES) procedure is an innovative approach to treating colorectal cancer that offers several advantages. First, the NOSES technique is minimally invasive, reducing the incidence of postoperative complications such as wound infection and fat liquefaction. Second, it provides excellent pain relief and improves cosmetic outcomes by requiring fewer abdominal incisions, thereby increasing patient satisfaction. Additionally, NOSES provides all of the advantages of minimally invasive surgery and enables patients to recover quickly, helping patients return to their normal lives faster. This approach aligns with the concept of patient-centered care and significantly improves patient quality of life. The positive results noted at both short- and long-term postoperative follow-up indicate that NOSES is a valuable option in cancer care. Despite its many benefits, NOSES has also been challenged by bacteriology, oncology, and ethics. This paper presents a review of recent research progress regarding NOSES in the treatment of colorectal cancer. In this article, we examined the advantages and disadvantages of NOSES in clinical practice and discussed potential issues and solutions.

Introduction

Since its inception in the 1990s, laparoscopic colorectal surgery has become the main surgical approach for colon cancer resection because it is characterized by less trauma and faster postoperative recovery. It has undergone continuous development and has been implemented in clinical practice over the last 20 years by national and international physicians. These trends emphasize that the development of minimally invasive surgical methods is necessary. However, laparoscopic colorectal surgery requires a long incision of approximately 3–5 cm on the lower abdomen to remove the specimens and for instrumental operation entry. Despite the significant reduction in surgical incisions compared with traditional open surgery, many patients still experience obvious postoperative incisional pain, infections, and other complications^[1]. This not only greatly diminishes the quality of being minimally invasive, which is considered an advantage of laparoscopic surgery, but also affects the aesthetics of the patient as well as their mental health.

In this context, natural orifice specimen extraction surgery (NOSES) has emerged. The most significant difference between NOSES and traditional laparoscopic surgery is that it avoids the need for a 3–5 cm auxiliary incision in the abdominal wall to extract the specimens. This reduction in the surgical incision minimizes damage to the abdominal nerves and other tissues. Consequently, postoperative pain in patients is alleviated substantially, and the risks of incisional infection, incisional hernia, and incisional tumor implantation are also reduced^[2–4]. The specimens are entirely removed through natural orifices such as the anus (or vagina) using intracorporeal anastomosis, resulting in less trauma and quicker recovery. As such, NOSES represents an improvement over traditional laparoscopic surgery, particularly since it is less invasive^[2,5].

Research on NOSES is still in its early stage, usually focusing on the exploration of contraindications and indications, as well as the innovation and reclassification of surgical procedures. Moreover, there are several associated controversies. The indications, safety, and long-term benefits to patients associated with the operation require studies with larger sample sizes and more data. Current studies have focused mainly on short-term results concerning bacteriological problems, oncological safety, incisional pain, hospitalization time, and the rate of early complications after NOSES. However, there is a lack of multicenter studies and relevant reviews on the long-term survival rate and quality of life of patients after NOSES, as well as potential issues, such as rectal–anal, urinary, and sexual functional impairment. This article aimed to introduce the current status of NOSES development and discussed the short-term and long-term patient benefits of laparoscopic colorectal cancer NOSES compared with those of conventional laparoscopic surgery, as indicated by domestic and international research reports. Furthermore, existing issues associated with NOSES and feasible improvement measures were explored.

Development and current status of NOSES

NOSES is a procedure that avoids the need for additional incisions in the abdominal wall by using laparoscopy, robots, transanal endoscopic microsurgery, soft endoscopes, and other equipment to draw specimens out through natural body cavities (rectum, vagina, or mouth) to complete various conventional surgeries in the abdominal and pelvic cavities (excision and reconstruction). In 2000, Kalloo et al^[6] described a new method of diagnosing and operating in the abdomen through the stomach in a pig model, known as natural orifice transluminal endoscopic surgery (NOTES). The implementation of NOTES involves entering the natural cavity through the mouth or stomach to perform endoscopic surgery, thereby avoiding surface scars and demonstrating the “scarless” concept of surgery, which represents a new approach to minimally invasive surgery. Building upon this, Palanivelu et al^[7] and others formally proposed the concept of NOSES as an approach to natural cavity endoscope surgery in the abdomen. In 2010, Wang et al^[8] successfully completed two procedures involving vaginal–rectal NOTES, which showed significant postoperative benefits. Inspired by this, Wang et al combined traditional laparoscopic technology with NOTES’s “scarless” concept to carry out “pseudo-NOTES surgery” for colorectal cancer, termed colorectal cancer NOSES. In the second decade of the 21st century, doctors innovatively combined robotic surgery with colorectal cancer NOSES to improve patient outcomes^[9]. In 2017, the Chinese NOSES Alliance, led by Wang et al, issued an expert consensus, which was later updated in 2019. Since then, NOSES surgery has had a unified definition and standard in China, marking a new era in the development of NOSES surgery.

NOSES can be divided into three types of surgery on the basis of the specimen retrieval pathway: transanal NOSES, transvaginal NOSES, and transoral NOSES. Colorectal NOSES primarily involves transanal and transvaginal specimen retrieval (Fig. 1). The transanal path is mainly suitable for patients with smaller specimens that are easy to remove and is the most commonly used path to retrieve specimens in colorectal NOSES. The transvaginal path has better extensibility, is easier to heal, can reduce the incidence of anal dysfunction, and is mainly suitable for female patients whose specimens are larger and cannot be removed transanally^[10–13].

Figure 1.

Two main pathways in CRC-NOSES. (A) Side views showing overall anatomical differences between transanal-NOSES and transvaginal-NOSES. (B) Transanal specimen extraction at the rectal stump, which mainly used for lower rectal cancer surgery. (C) Specimen extraction through rectal incision, which mainly used for middle rectal cancer surgery. (D) Schematic representation of transvaginal specimen extraction.

The procedures involved in NOSES are subdivided into three types on the basis of the method of specimen retrieval:^[1] eversion resection,^[2] pull-out resection, and^[3] drag-out resection. Eversion resection is mainly used for lower rectal resection, whereas pull-out resection is mainly used for mid-rectal resection, and drag-out resection can be applied to the upper rectum, sigmoid colon, left hemicolon, right hemicolon, and total colectomy. The first two resections are performed outside the abdominal cavity, whereas the last one is performed in the abdominal cavity. According to a 2019 expert consensus, 10 types of procedures were classified on the basis of the surgical site, method of surgery, pathway of specimen retrieval, and method of specimen retrieval (Table 1).

Table 2.

Basic characteristics of the included studies (meta-analyses excluded).

Reference	Country/area	Patients (NOSES/CL)	Agea, years NOSES/CL)	Gender (NOSES/CL) (M/F)		BMIa, kg/m2 (NOSES/CL)	Tumor sizea, cm (NOSES/CL)	Approach	cTNM	nCRT (NOSES/CL)	Location (NOSES/CL) (RC/LC/SC/REC)		Tumor height from anal vergea, cm (NOSES/CL)	Important short-term prognosis (NOSES group)	Important long-term prognosis (NOSES group)
Kim et al [12]	Korea	58/58	62.8 ± 9.0/63.2 ± 10.7	0/58	0/58	23.5 ± 2.9/23.2 ± 3.3	3.4 ± 1.8/3.7 ± 1.8	TV	I–III	0/0	0/0/21/37	0/0/22/36	NA/NA	Longer operative time; less pain; shorter flatus passage time; better cosmetic results	No difference in DFS at 3 years
Zhang et al[15]	China	196/243	61.36 ± 13.27/60.35 ± 11.08	90/106	145/98	22.53/23.26	3.68 ± 1.59/NA	TS	0–IV	0/2	NA	NA	NA/NA	Less blood loss; shorter flatus passage time; less protective ileostomy	No difference in OS and DFS at 5 years
Zheng et al[16]	China	92/90	61.05 ± 10.14/59.58 ± 10.98	47/45	44/46	24.09 ± 3.19/25.12 ± 3.92	NA	TS	NA	NA	0/0/0/92	0/0/0/90	11.94 ± 6.19/	Longer operative time; shorter drainage tube retention time; shorter postoperative hospital stays	NA
													11.50 ± 3.49
Ding et al[19]	China	43/43	56.48 ± 10.23/58.02 ± 9.66	25/18	22/21	23.6 ± 3.1/23.2 ± 3.4	3.1 ± 1.7/3.6 ± 1.9	TS	I–III	0/0	0/0/13/30	0/0/16/27	13.8 ± 5.5/	Less blood loss; less pain; shorter postoperative exhaust time and regular diet time; better cosmetic results	No difference in the rate of tumor recurrence and 45-month DFS after surgery
													14.3 ± 6.1
Wolthuis et al[20]	Belgium	20/20	54 (31–72)/58 (40–73)	5/15	10/10	23.5 (18–29)/24 (20–29)	NA	TS	NA	0/0	0/0/20/0	0/0/20/0	NA	Longer operative time; more treatment costs; less pain; higher levels ofinflammatory response; better cosmetic results	No difference in Cleveland Clinic Incontinence Scores and anal manometry recordings at 3 months
Zhu et al[21]	China	104/119	61.4 ± 12.3/62.5 ± 12.1	50/64	65/56	23.2 ± 1.6/24.4 ± 3.7	3.2 ± 1.2/3.6 ± 1.4	TS	I–III	0/0	0/0/0/104	0/0/0/119	11.1 ± 8.3/	Longer operative time; less blood loss; faster bowel function recovery; shorter postoperative hospital stays; less pain; lower complication rate	No difference in DFS at 40 months; better quality of life at 6 months after operation
													13.0 ± 11.1
Leung et al[22]	Hong Kong	35/35	62 (51–86)/72 (49–84)	13/22	12/23	NA	2 (2–4)/3 (2–4)	TS	I–IV	NA	NA	NA	NA	Lower maximum pain score; less wound infection	NA
Zhou et al[23]	China	100/119	60.14 ± 11.2/61.2 ± 10.4	49/51	63/56	23.3 ± 2.6/23.4 ± 2.7	3.2 ± 1.2/3.5 ± 1.5	TS	I–III	0/0	0/0/0/100	0/0/0/119	2.5 ± 1.2/2.4 ± 1.3	Longer operative time; less blood loss; faster bowel function recovery; less pain; shorter postoperative hospital stays; lower complication rate	No difference in DFS at 3 years
Hisada et al[24]	Japan	20/50	63.7 ± 9.0/66.3 ± 11.0	12/8	NA	NA	2.7 ± 0.9/3.85 ± 1.8	TS	I–III	NA	0/0/0/20	0/0/0/50	NA	Less frequent use of analgesics; shorter duration of pain	No local recurrence or distant metastasis in 30 months
Zhou et al[26]	China	52/52	55.6 ± 10.4/57.0 ± 10.7	27/25	27/25	22.7 ± 2.7/23.1 ± 2.9	3.4 ± 1.3/3.7 ± 1.0	TS	I–III	8/10	0/0/21/41	0/0/20/32	NA	Shorter time to passage of flatus; less pain; less frequent use of analgesics; higher levels of inflammatory response;	No difference in OS and DFS at 5 years
Hu et al[27]	China	26/26	63.1 ± 8.3/61.5 ± 7.6	17/9	15/11	26.5 ± 4.7/26.4 ± 4.6	NA	TS	I–III	0/0	0/0/0/26	0/0/0/26	4.9 ± 0.7/4.9 ± 0.6	Faster bowel function recovery; shorter postoperative hospital stays; less pain; less frequent use of analgesics; better cosmetic results	NA
Zhang et al[28]	China	65/132	56.1 ± 9.3/55.5 ± 9.5	32/33	57/75	23.7 ± 2.9/23.1 ± 3.1	2.9 ± 1.5/3.7 ± 1.7	TS	I–III	0/0	0/0/27/38	0/0/46/86	14.1 ± 6.1/14.1 ± 6.6	Less blood loss; shorter time to passage of flatus; shorter time to first defecation; shorter time to ambulation; shorter postoperative hospital stays; less pain	No difference in bowel function
Liu et al[32]	China	356/412	64 (29–79)/62 (32–81)	192/164	235/177	22 (17–31)/23 (18–32)	3 (1–7)/4 (1–9)	TS	I–III	17/31	0/0/0/356	0/0/0/412	NA	None	None
Gao et al[35]	China	45/45	58.1 ± 11.8/59.1 ± 10.8	0/45	0/45	22.1 ± 2.7/21.6 ± 2.2	3.5 ± 1.3/3.6 ± 1.2	TV	I–III	NA	0/0/16/29	0/0/18/27	NA	Longer operative time; less pain; less frequent use of analgesics; shorter time to first flatus	No difference in OS and DFS at 3 years
Awad et al[36]	USA	20/20	66.9 ± 8.90/63.6 ± 9.08	0/20	0/20	25.1 ± 6.65/31.6 ± 8.33	4.735 ± 3.61/3.42 ± 1.16	TV	I–III	NA	20/0/0/0	20/0/0/0	NA	Longer operative time; better cosmetic results	None
Tang et al[38]	China	186/186	59.0 ± 10.4/59.9 ± 11.3	94/92	92/94	22.9 ± 2.8/22.8 ± 3.2	NA	TS	I–III	0/0	15/7/31/133	17/9/25/135	NA	Less blood loss; less pain; less frequent use of analgesics; faster bowel function recovery; shorter postoperative hospital stays; less Postoperative complication	No difference in OS and DFS at 5 years; better quality of life at 3 months after operation; no difference in anal function at 6 months after operation
Zhang et al[41]	China	39/39	72.7 ± 5.8/71.4 ± 5.1	19/20	20/19	21.5 ± 3.2/22.9 ± 3.0	NA	TS	I–III	0/0	0/0/7/32	0/0/13/26	NA	Less pain; shorter time to first flatus; better cosmetic results; less postoperative complication	No difference in OS, DFS, LR rates and DM rates at 5 years; better quality of life at 3 months after operation; no difference in anal function at 6 months after operation
Park et al[42]	Korea	138/138	60.3 ± 10.6/60.4 ± 11.3	32/106	41/97	23.4 ± 2.9/23.3 ± 3.2	3.36 ± 1.73/3.54 ± 1.90	TS/TV	0–III	8/10	0/0/0/138	0/0/0/138	NA	Longer operative time; less blood loss; shorter time to resume regular diet; shorter postoperative hospital stays	No difference in DFS and LR rates at 3 and 5 years
Denost et al[43]	France	122/98	63 (20–90)/65 (25–85)	70/52	69/29	24.3 (17.3–33.6)/25.8 (18.8–38.3)	3.9 (1–10)/4 (1–15)	TS	0–III	104/88	0/0/0/122	0/0/0/98	4 (1–6)/4 (1.5–6)	NA	No difference in OS, DFS and LR rates at 5 years; no difference in anal function at 2 years
Ng et al[44]	China	35/38	65.14 ± 9.14/63.95 ± 9.19	20/15	11/16	22.64 ± 1.95/23.41 ± 1.60	3.05 ± 0.92/3.25 ± 0.99	TS	I–III	14/12	0/0/24/11	0/0/20/18	17.31 ± 5.56/15.61 ± 5.39	Less blood loss; longer operative time; similar operative time	NA
Bu et al[45]	China	46/46	66.26 ± 13.34/65.33 ± 10.68	25/21	26/20	21.80 ± 2.78/21.76 ± 2.39	NA	TS	I–III	0/0	14/2/12/18	16/3/10/17	NA	Similar operative time; less pain; better cosmetic results; similar total medical costs	No difference in OS and DFS at 5 years; similar quality of life
Chang et al[46]	Taiwan	94/94	63.5 ± 12.8/63.9 ± 13.1	51/43	55/39	23.8 ± 4.4/23.9 ± 3.7	3.0 ± 1.4/3.0 ± 1.5	TS	I–III	NA	0/0/66/28	0/0/68/26	NA	Longer operative time; shorter time to first flatus; shorter postoperative hospital stays	No difference in OS, DFS and LR rates at 5 years
Zhou et al[47]	China	172/172	59.3 ± 11.0/59.2 ± 8.4	103/69	105/67	23.2 ± 3.1/23.0 ± 2.7	3.5 ± 1.4/3.6 ± 1.2	TS	I–III	NA	0/0/64/108	0/0/65/107	NA	Longer operative time; less pain; less frequent use of analgesics; less wound infection; shorter time to first flatus	NA
ReDati et al[48]	China	24/24	59.5 ± 2.1/59.8 ± 2.3	21/3	19/5	22.9 ± 3.0/23.2 ± 3.1	3.1 ± 1.2/3.3 ± 1.5	TS	I–III	0/0	24/0/0/0	24/0/0/0	NA	Less wound infection; shorter time to first flatus; less pain	No difference in OS, DFS and LR rates at 5 years
Zhong et al[49]	China	38/38	57.8 ± 10.3/60.3 ± 9.6	21/17	20/18	22.7 ± 2.5/23.3 ± 2.6	NA	TS	I–III	0/0	0/0/0/38	0/0/0/38	NA	Less blood loss; shorter time to first flatus; shorter regular diet time; less pain	No difference in OS, DFS and LR rates at 3 years; no difference in OS and DFS at 5 years
Yu et al[51]	China	36/128	62 ± 7/61 ± 8	20/16	70/58	23.0 ± 1.7/23.4 ± 1.7	4.2 ± 0.5/4.6 ± 0.6	TS	I–III	NA	0/0/15/21	0/0/60/68	NA	Less pain; shorter postoperative hospital stays; lower incidence of the incisional infection; similar total medical costs	No difference in OS at 3 and 5 years
Zheng et al[54]	China	52/48	≤60: 33; >60: 19/ ≤ 60: 30; > 60: 18	0/52	0/48	≤23: 28; > 23: 24/ ≤ 23: 25; > 23: 23	NA	TV	I–II	NA	0/0/0/52	0/0/0/48	≤10: 28; ≥10: 24/≤ 10: 26; > 10: 22	Less blood loss; shorter postoperative hospital stays; less pain; shorter time to first flatus; shorter time to resume regular diet	More number of lymph nodes retrieved; no difference in sexual function quality at the third postoperative month; higher in OS at 2 years; better quality of life at 6 months after operation
Zheng et al[58]	China	92/92	61.67 ± 8.56/60.45 ± 9.07	43/49	45/47	23.97 ± 2.86/23.75 ± 3.45	3.65 (3–4)/4 (3–4)	TS	I–III	NA	0/0/40/52	0/0/25/67	NA	None	Higher positive rate of bacterial culture; no difference in postoperative peritoneal washings’ tumor cytology results; no difference in DFS at 2 years; no significant correlation between positive bacterial culture and intra-abdominal infection
Ouyang et al[59]	China	96/89	58 ± 11/61 ± 11	44/52	49/40	22.5 ± 2.9/22.9 ± 2.6	NA	TS	0–III	0/0	2/3/10/81	5/3/19/62	NA	Less pain; less frequent use of analgesics; shorter postoperative hospital stays; lower incision-related complications rate	No difference between bacteriological and oncologic positive results; no difference in LR rates at 2 years
Liu et al[60]	China	50/75	60.68 ± 9.90/58.00 ± 10.11	29/21	45/30	23.35 ± 4.11/23.86 ± 3.82	3.29 ± 1.00/3.53 ± 1.01	TS	I–III	0/0	0/0/23/27	0/0/34/41	NA	Higher levels of inflammatory response	No difference betweenbacteriological and oncologic positive results

BMI, body mass index; CL, conventional laparoscopic surgery; cTNM, clinical TNM stage; F, female; LC, left colon; M, male; NA, not available; nCRT, neoadjuvant chemoradiotherapy; NOSES, natural orifice specimen extraction surgery; RC, right colon; REC, rectum; SC, sigmoid colon; SD, standard deviation; TS, transanal; TV, transvaginal.

There was no statistically significant difference between NOSES and CL in this regard.

^aMean ± SD or median (range).

Table 1.

Colorectal cancer NOSES procedures and classifications^[14].

Classification (CRC-NOSES)	Modus operandi	Tumor location	Orifice
I	Laparoscopic lower rectal cancer resection with transanal specimen extraction	Lower rectum	Anus
II	Laparoscopic middle rectal cancer resection with transanal specimen extraction	Middle rectum	Anus
III	Laparoscopic middle rectal cancer resection with transvaginal specimen extraction	Middle rectum	Vagina
IV	Laparoscopic upper rectal cancer resection with transanal specimen extraction	Upper rectum/distal sigmoid colon	Anus
V	Laparoscopic upper rectal cancer resection with transvaginal specimen extraction	Upper rectum/distal sigmoid colon	Vagina
VI	Laparoscopic upper rectal cancer resection with transanal specimen extraction	Left colon/proximal sigmoid colon	Anus
VII	Laparoscopic left colectomy with transvaginal specimen extraction	Left colon/proximal sigmoid colon	Vagina
VIII	Laparoscopic right colectomy with transvaginal specimen extraction	Right colon	Vagina
IX	Laparoscopic total colectomy with transanal specimen extraction	Total colon	Anus
X	Laparoscopic total colectomy with transvaginal specimen extraction	Total colon	Vagina

Indications and contraindications for colorectal cancer NOSES

The 2019 expert consensus describes the prerequisites and conditions for the implementation of colorectal cancer NOSES. First, since NOSES is essentially laparoscopic surgery, the fundamental requirements of routine laparoscopy should be met, including the following^[1]: the surgical team has rich experience in laparoscopic surgery and can master digestive tract reconstruction under total laparoscopy^[2]; the surgery cannot be used for locally advanced tumors (the primary tumor invaded the muscular layer of the bowel wall or had lymph node metastasis without distant metastasis)^[3]; the surgery is not suitable for acute intestinal obstruction and intestinal perforation caused by the tumor; and^[4] a whole abdominal exploration needs to be conducted with consideration of preoperative lesion localization. The risk of abdominal contamination and tumor metastasis and whether it can improve patient prognosis are important considerations prior to performing NOSES. Therefore, selecting the right patient population is an important prerequisite for the success of NOSES.

Second, the surgeon needs to ensure preoperatively that the target specimen can be removed through the natural orifice selected. This is a specific indication for NOSES and considers the following:^[1] the tumor infiltration depth is applicable to T2–T3 stage and large T1 tumors, as well as cases where local excision has yielded unsatisfactory results^[2]; for specimen retrieval through the anus, the maximum circumferential diameter of the specimen should not exceed 5 cm, and for vaginal retrieval, the maximum circumferential diameter should not exceed 7 cm; and^[3] the surgical plan should be adjusted according to the degree of mesenteric obesity and the size of the natural orifice.

The type of procedure selected is directly related to the location of the tumor. Patient prognosis is similar when appropriate procedures are adopted according to the tumor location. In 2022, Zhang et al identified the location of tumors in patients with colorectal cancer and subdivided them into the upper rectum (the distal margin of the tumor, 10–15 cm from the edge of the anus), middle rectum (5–10 cm from the anus), or lower rectum (<5 cm from the anus)^[15]. Tumors in the upper rectum were subjected to the drag-out resection method, those in the middle rectum were subjected to the pull-out resection method, and those in the lower rectum were subjected to the eversion resection method. Patients treated with these three methods and those treated with conventional laparoscopic surgery for colorectal cancer were divided into four groups for this retrospective study. The authors reported that the three different NOSES methods had similar results in terms of hospital stay length, first postoperative flatus time, number of lymph nodes cleared, and complication rates. Although these findings suggest that patients who underwent surgery via the three different methods have similar prognoses, the American Joint Committee on Cancer staging of patients who underwent surgery via the three different methods in this study differed, and more research is needed to further elucidate the prognostic differences among the different NOSES methods.

The relative contraindications for NOSES include^[14] the following: those who cannot tolerate laparoscopic surgery, those whose specimens are too large to be removed via natural orifices, those with a thick mesentery, and obese patients (body mass index [BMI] ≥30 kg/m²). Those with anal diseases or anal stenosis are not suitable for anal specimen retrieval, and those with gynecological inflammation or vaginal atresia and other deformities are not suitable for vaginal specimen retrieval. Vaginal NOSES may also affect the integrity of the vaginal wall; thus, women who plan to give birth in the future might be reluctant to undergo vaginal NOSES. In addition, recent evidence suggests that diabetes can affect the prognosis of NOSES patients, as a meta-analysis by Zheng et al revealed that diabetes is positively correlated with the risk of abdominal infection after NOSES surgery^[16].

According to the 2017 expert consensus, the maximum circumferential diameters of the specimens retrieved via the anus and vagina were <3 and <5 cm, respectively. However, with the extensive exploration of NOSES in various medical centers, the 2019 expert consensus supplemented and improved this requirement, expanding it to <5 cm for anal samples and 5–7 cm for vaginal samples. The consensus further allows experienced surgical teams to explore and carry out special types of NOSES. Therefore, the author believes that the indications for NOSES surgery will become more extensive in the future.

Advantages of NOSES

Short-term prognosis of NOSES

The greatest advantage of NOSES is that it eliminates the need to create a 5 cm incision on the patient’s abdomen for sample extraction, which is the greatest surface trauma in conventional laparoscopic surgery. As a result, patients avoid infections and inflammatory responses associated with incisions and experience substantially less postoperative pain and postoperative complications, along with a reduced recovery time and length of hospital stay, which lowers medical costs. Compared with conventional laparoscopy, NOSES also has significant cosmetic benefits.

Incision infection and complication rates

NOSES does not involve an incision in the abdominal wall for sample extraction, which fundamentally reduces incision-related complications^[17]. Studies have shown that patients who undergo NOSES have lower postoperative infection rates and incision infection rates than those who undergo conventional laparoscopy, and the reduction in incision complications has been identified as the main cause of the decrease in the rate of postoperative complications^[18–22]. The overall complication rate in the NOSES group was significantly lower than that in the conventional laparoscopic surgery group; moreover, the postoperative complication rates of anal NOSES and vaginal NOSES were not significantly different, and both were lower than those in the conventional laparoscopy group^[3,4,23]. However, a few studies have reported that the difference in complication rates between NOSES and conventional laparoscopy is not significant^[20,24]. Although a small number of studies have confirmed that the postoperative complication rate of NOSES is similar to that of conventional laparoscopy, at least in this respect, NOSES still has special advantages over conventional laparoscopy, and the difference between the two may become increasingly apparent with additional studies.

Postoperative pain

NOSES has a very obvious advantage over conventional laparoscopy in terms of controlling postoperative pain. Many studies have assessed postoperative pain via a visual analog scale and reported that the scores of patients undergoing NOSES are significantly lower than those of patients undergoing conventional laparoscopic surgery^{[21,23,25–29]}. Moreover, not only are VAS scores significantly lower among patients who undergo NOSES on the first day after surgery, but the proportion of patients requiring additional analgesics after NOSES is also lower than that of patients who undergo conventional laparoscopy^[3]. Therefore, NOSES has been shown to greatly reduce postoperative pain, which is very important as a short-term benefit. Some studies have shown that severe postoperative pain is a risk factor for a poor long-term prognosis^[30]. Reducing postoperative pain and effective pain control are important factors in reducing postoperative stress levels. The neuro-humoral stress response is composed of an inflammatory cascade, which, once activated, can adversely affect postoperative complications, recovery, and hospital stays^[31].

Gastrointestinal function recovery time

Numerous studies have shown that NOSES for colorectal cancer patients has a discernible advantage in recovering gastrointestinal function. Compared with conventional laparoscopy, NOSES involves faster first-time flatus, faster first-time defecation, and a quicker return to regular eating after surgery^{[19,21,25,26,32]}. The faster recovery of gastrointestinal function in NOSES patients may be due to the avoidance of an abdominal wall incision.

Enhanced recovery after surgery (ERAS) refers to a perioperative bundle of multimodal strategies aimed at optimizing patient care, with the ultimate goal of improving clinical outcomes and reducing the surgical stress response, thereby facilitating patient recovery^[33]. The operation of NOSES coincides with the principles of ERAS and can accelerate the recovery of patients in the context of ERAS. Compared with conventional laparoscopy, NOSES not only reduces intraoperative bleeding, but also, compared with traditional open surgery, NOSES maintains a relatively independent environment in the abdomen, and the organs inside the abdomen will not come into contact with the external environment; therefore, disturbances to the patient’s abdominal cavity environment are minimal^[25,34]. However, most of these studies are single-center studies, which have certain limitations, and more large-sample multicenter research data are needed to confirm these findings.

Length of stay

Another significant advantage of NOSES is that it reduces hospital stay, allowing patients to return to normal work and life as soon as possible, which also improves the efficiency of hospital operations. Multiple studies have shown that the hospital stay of NOSES patients is significantly shorter than that of patients in conventional laparoscopic surgery groups^{[3,21,26,28,35]}. However, a few studies have indicated that NOSES does not reduce the hospital stay^[36], which might be due to limited understanding and incorrect care when NOSES was first implemented as a new surgical procedure. More recent studies, however, have shown that NOSES shortens hospital stays^[25,37]. The length of hospital stay reflects patient recovery and is an important index of patient postoperative recovery and hospital bed turnover.

Medical treatment expense

Patient treatment costs are often associated with the complexity of the surgery and the number of days of hospitalization. A Belgian study by Wolthuis et al^[20] reported that while patients who underwent NOSES had a significantly shorter hospital stay than patients who underwent conventional laparoscopy did, the total treatment costs were greater for the NOSES group. Since the abdominal anastomosis in NOSES uses a delta-shaped anastomosis, multiple staplers are needed, which significantly increases the operation cost. At the same time, the evidence also suggests that the total treatment costs of the two procedures are similar^[38]. This is because, although NOSES is more expensive than conventional laparoscopic surgery is, NOSES reduces the number of days in hospital and the rate of surgical incision infection, which would otherwise significantly increase healthcare expenditures and recovery time. As NOSES avoids the need for abdominal wall incisions, it can effectively prevent incision infections, greatly reduce the occurrence of complications, shorten the length of hospital stay, and possibly reduce overall treatment costs.

Cosmetic benefits

NOSES eliminates the need for a large abdominal wound, leaving only a few trocar holes after surgery, which is beneficial for the aesthetics of the patient’s abdomen. In 2009, Peterson et al^[39] evaluated the willingness of women to undergo NOSES, along with the associated reasons for undergoing NOSES, and found that younger women placed greater value on the cosmetic benefits of NOSES. Wolthuis et al^[40] reported a cosmetic effect score and satisfaction survey of patients who underwent NOSES surgery. Patients were asked to complete a Body Image and Cosmetic Score questionnaire and a Patient Scar Assessment Questionnaire. The scores for postoperative appearance, scar awareness, and appearance satisfaction were better in the NOSES group than in the conventional laparoscopy group. In recent years, elderly patients undergoing NOSES have also been found to benefit in terms of cosmetic effects and mental health^[41].

Long-term prognosis in patients with NOSES

In addition to the immediate benefits of avoiding an abdominal incision, there is equal concern over the long-term prognosis of patients after NOSES surgery, including the effectiveness of oncological treatment, overall survival, postoperative quality of life, and occurrence rate of anal function disorders. Recent multicenter studies have greatly expanded the knowledge regarding the long-term benefits of NOSES, such as urinary function and satisfaction with sexual life.

Safety of oncological treatment

Numerous studies and analyses have shown that there is no significant difference between patients who undergo NOSES and those who undergo conventional laparoscopy in terms of the circumferential margin^[27,42,43], distal margin^{[12,19,26,28]}, or proximal margin^[12,19,26]. The mean circumferential margin was 6.9 ± 3.9 mm in the conventional laparoscopy group and 7.8 ± 5.6 mm in the NOSES group (n = 242). The circumferential margin was invaded (less than 1 mm) in two NOSES patients and three conventional laparoscopy patients (1.4% vs. 2.2%, P = 0.685). The mean distal margin was 4.9 ± 3.5 cm in the conventional laparoscopy group and 4.2 ± 2.4 cm in the NOSES group (n = 116, P = 0.155). The mean proximal margin was 12.3 ± 10.0 cm in the conventional laparoscopy group and 13.0 ± 11.6 cm in the NOSES group (n = 116, P = 0.683). There was also no significant difference in the length of the specimens removed by the two procedures^[19,26,44]. The mean length of the specimens was 15.5 ± 4.8 cm in the conventional laparoscopy group and 15.3 ± 5.4 cm in the NOSES group (n = 104, P = 0.845).

Lymphatic metastasis is the main metastatic route of colorectal cancer, and the extent of lymph node dissection is directly related to long-term patient prognosis. The Chinese colorectal cancer diagnosis and treatment guidelines (2023 version) suggest removing all possibly affected lymph nodes. In radical surgical specimens without neoadjuvant treatment, at least 12 lymph nodes were detected, and there was no significant difference in the number of lymph nodes dissected between the NOSES group and the control group^[45–47]. However, meta-analyses that included more NRCTs suggested that the number of harvested lymph nodes in the NOSES group was significantly greater than that in the conventional laparoscopy group (Weighted Mean Difference [WMD] = −0.91; 95% Confidence Interval [C]I [−1.76, −0.06]; I² = 0%; Z = 2.09; P = 0.04)^[25].

Overall survival and disease-free survival

Multiple studies have shown that there is no significant difference in 3-year overall survival or 3-year disease-free survival between patients who undergo NOSES and those who undergo traditional laparoscopy^[3,21,23,48]. A study by Zhou et al^[26] conducted a longer follow-up and reported that the 5-year overall survival and 5-year disease-free survival rates of the NOSES group and the conventional laparoscopy group were similar after a maximum follow-up of 83 months. Indeed, many studies have shown that the 5-year overall survival rate and 5-year disease-free survival rate are not significantly different between patients who undergo NOSES and those who undergo conventional laparoscopy^{[26,42,43,46,49]}.

Quality of life

Patients receiving NOSES, traditional open surgery, or conventional laparoscopy have been compared in certain studies. Six months after surgery, quality of life was evaluated using the SF-36 quality of life questionnaire. The outcomes demonstrated that patients who had NOSES had the highest quality of life and that their scores for physical function, pain, social function, emotional expression, and mental health were all higher than those of patients who had the other two types of procedures^[21,50]. Specifically, Wolthuis et al^[20] employed the Cleveland Clinic Incontinence Score (CCIS) in a randomized clinical trial to assess patients’ urinary function in two groups: one that underwent traditional laparoscopy and the other, NOSES. In both groups, the median CCIS values prior to surgery, 6 weeks following surgery, and three months following surgery were comparable. Because the rectum and anus are anatomically near the lower urinary system, surgical procedures that harm one of them may also harm the urethra.

Postoperative anal function

Multiple studies using different evaluation methods have reported similar postoperative anal function in patients in the NOSES group and the conventional laparoscopy group^{[20,27,42,48]}. Although NOSES for colorectal cancer does not require an abdominal wall incision, the removal of tumor specimens occurs through the anus, which has limited extensibility. If the tumor is too large, it is very likely to cause organic damage, leading to anal dysfunction, which affects the long-term prognosis of patients. Notably, obese patients are more prone to postoperative anal dysfunction under the same conditions^[14] because of visceral fat accumulation and increased abdominal pressure.

Safety of NOSES

Safety has always been the focus of surgical science. Severe perioperative complications not only exacerbate the physical and mental pain of patients but also prolong hospital stays, increase hospitalization costs, and may even lead to failure of the entire treatment, worsening patient prognosis. Although much evidence suggests that NOSES surgery is superior to conventional laparoscopic surgery in terms of incision infection, postoperative pain, hospital stay, and postoperative recovery, some specific concerns about the safety of this technique remain.

The issue of surgery time

Many studies have shown that compared with conventional laparoscopic surgery, the operation time of NOSES for radical resection of colorectal cancer is longer, and there is less intraoperative bleeding^{[3,21–23,38]}. In particular, the meta-analysis of Wang et al^[3], which included 14 studies, revealed that the operation time of NOSES was significantly longer than that of conventional laparoscopy (WMD = 13.09, 95% CI [7.07, 19.11]; I² = 66.6%; Z = 4.26; P < 0.001). However, several other studies have shown that the operation times of the two methods are similar^[26,32,51]. Generally, intraoperative blood loss is positively correlated with operation time; the longer the operation time is, the more blood the patient may lose. However, it is also acknowledged that NOSES involves less blood loss, which challenges the traditional view. This may be because the trauma caused by NOSES is less severe, which can allow skilled doctors to quickly identify small hemorrhages in the abdominal cavity and stop the bleeding.

The surgical field of NOSES is narrower than that of traditional open surgery, which may require more time for gastrointestinal anastomosis, especially when the surgery is challenging or when the surgeon is not experienced with the colorectal NOSES procedure. The extension of the operation time will inevitably increase the risk of bacterial infection at the anastomosis site, thereby affecting anastomosis healing and prolonging the postoperative recovery time. The duration of the operation also relates to the patient’s own health status (e.g., the presence of obesity, edema, or cardiovascular diseases), which may increase the operation time. However, the most critical factors are often the proficiency of the chief surgeon and the difficulty of the surgery. This poses greater technical requirements for the surgical team.

Specimen collection path selection

The extraction of samples through natural orifices is the most innovative technique and the most important feature of NOSES surgery and remains a main focus as well as the subject of debate. Related studies have investigated whether anal extraction of specimens causes postoperative anal dysfunction in patients. Although considerable research has shown that there is no significant difference in anal dysfunction between NOSES patients and conventional laparoscopic group patients, there have been cases where the surgical approach had to be changed to conventional laparoscopic surgery because the tumor was discovered to be too large during the operation^{[20,27,42,43,52]}. The academic consensus is that a tumor with a diameter that is too large will damage the anus; thus, it is necessary to strictly stipulate the maximum tumor diameter that can be removed through the anus to preserve its function.

According to the 2017 version of the expert consensus on the extraction of colorectal tumors through natural orifices, the anus is the ideal natural orifice for extracting various colorectal specimens, which aligns with the objective and requirements of minimally invasive surgeries such as NOSES. The 2019 expert consensus^[14] further noted that there are two ways to extract specimens through the rectum and anus: extraction through the rectal end and extraction through a rectal incision. Extraction through the end is currently the most widely used and least harmful approach to specimen extraction. Extraction through an incision is mainly suitable for patients who undergo left half or right half colectomy. This method requires an additional rectal incision, which inevitably increases the risk of intestinal leakage. Therefore, the preoperative evaluation of the patient’s condition must be comprehensive and accurate, and the indications and contraindications for NOSES must be strictly controlled. Specimen extraction through the anus is not limited by sex and has the additional advantage of facilitating the construction of the anastomosis. When choosing between vaginal and anal specimen extraction, the latter is usually the first choice. However, further research on whether repeated anal operations increase the risk of anal dysfunction is needed.

Compared with the anus, the vagina is also considered an ideal orifice. Vaginal surgery facilitates the removal of larger samples because of the vagina’s high elasticity, rich blood supply, and good healing ability. In addition, for gynecological tumors, vaginal specimen extraction is less traumatic and more reasonable than anal extraction. The safety of the transvaginal approach has been demonstrated in several studies, and it is believed that NOSES does not contribute to anastomotic leakage or impact sexual function^{[2,12,53–55]}. However, vaginal specimen extraction has the following limitations: first, this procedure is sex-specific and limited to female patients; second, incising the vaginal wall may increase the risk of postoperative complications; and third, it is unclear whether vaginal specimen extraction may increase the risk of pelvic infection, rectovaginal fistula formation, tumor metastasis, and the occurrence of gynecological diseases. Additional multicenter studies with large sample sizes are needed to address these questions. Finally, the use of vaginal NOSES is also limited by cultural sensitivity: since it may damage the hymen, vaginal specimen extraction may not be acceptable to some women.

Bacteriological problems

During the NOSES operation process, the intestine must be opened, and complete intraperitoneal intestinal reconstruction is performed, which directly damages the peritoneum and connects the abdominal cavity with the intestinal cavity. The staple base is directly inserted through the anus, which substantially destroys the abdominal sterility and is a cause of bacteriological concern. There might be a risk of peritoneal infection due to the possible presence of positive bacterial cultures in the abdominal fluid^[56]. Previous studies have confirmed the possibility of bacterial contamination during NOSES surgery by examining the bacteria cultured from intraoperative abdominal lavage fluid^[57]. However, previous studies included fewer samples and did not include control variables, such as comparisons with a conventional laparoscopic surgery group, suggesting insufficient evidence. In recent years, relevant research and guidelines have attempted to reexamine bacteriological issues and propose relevant solutions. There is evidence that the positive bacterial rate in the abdominal lavage fluid after NOSES was greater than after conventional laparoscopy (42.2% vs. 25.0%, P = 0.028, n = 184), but there was no significant difference in the incidence of abdominal infection or postoperative infection-related indicators between the two procedures (3.3% vs. 3.8%, P = 0.774, n = 184)^[58]. However, other researchers reported no difference in the percentage of positive bacteria in abdominal lavage fluid (65.3% vs. 67.4%, P = 0.67, n = 185) or intraperitoneal infection (4.2% vs. 3.4%, P = 1.00, n = 185) between the two procedures^[59,60].

The expert consensus recommends measures such as prophylactic use of antibiotics, mechanical bowel preparation, intraoperative abdominal lavage, massive amounts of povidone-iodine and saline rectal lavage, use of an intracavitary wound retractor, and placement of an abdominal drain to reduce the bacterial load of NOSES^[14]. Surgical objects, such as Hem-o-Lok clips, ligation devices, and specimen protection sheaths, are not inserted directly into the anus or rectum but are inserted into the abdomen through the trocar hole in the abdomen, after which the specimen is removed from the rectum in an antegrade manner, which potentially leads to fewer cases of abdominal infection^[16,23]. Although NOSES surgery may increase the rate of positive bacterial cultures in abdominal lavage fluid, it does not increase the risk of abdominal infection. On the basis of the principle of asepsis, surgeons meticulously design surgical methods, choose appropriate operations according to guideline recommendations and the specific conditions of the patients, and can largely avoid complications such as abdominal infection caused by fixed surgical procedures.

Oncological problems

While specimens are extracted during NOSES, tumor cells may shed and cause implantation metastasis in the abdominal or pelvic cavity. In addition, when a tumor is extracted from relatively narrow natural cavities such as the rectum, anus, and vagina, it inevitably undergoes compression, leading to the shedding of tumor cells, which further increases the possibility of metastasis. One study suggested that local recurrence after NOSES was actually implantation metastasis, which was closely related to the backflow of peritoneal lavage fluid, suggesting that there may be a certain number of tumor cells in the lavage fluid^[26]. Metastasis in the NOSES group in that study occurred because correct antireflux measures were not taken in the first eight patients. Surgeons should pay close attention to this oncological issue associated with NOSES. Intraoperative compression of the tumor in situ increases the risk of tumor recurrence and has adverse effects on patient prognosis^[61]. The surgical goal of NOSES should still be complete resection and intact removal of the tumor. Fortunately, methods for addressing bacteriological issues often also work for oncological problems, and there is considerable overlap between the two. The 2019 expert consensus recommends a series of procedures, such as the reasonable use of iodophor gauze to protect the intestinal end, the use of an intraoperative aspirator and postoperative drainage, rectal lavage with iodophor solution through the anus, abundant lavage of the rectal stump with saline containing iodophor, and the use of specimen protection sheaths, all of which can reduce the risk of abdominal contamination and tumor implantation. Studies have shown that when an appropriate surgical procedure is selected according to the patient’s condition and a series of protective measures are applied, such as a specimen protection sheath, the percentage of positive tumor cells in the postoperative abdominal lavage fluid in NOSES does not differ from that in conventional laparoscopy^[59,60]. Further univariate analysis revealed that the percentage of positive tumor cells in peritoneal lavage fluid was significantly related to the tumor infiltration depth and lymph node metastasis and could serve as an independent predictive factor for the percentage of positive lavage fluid cells. Long-term follow-up of 66 patients for more than 2 years revealed no significant difference in tumor recurrence rates among the patients in the two groups, and no significant difference was found in disease-free survival. There was no significant difference in the 3-year local recurrence rate between the NOSES and CL groups at different tumor stages (stage I: 2.5% vs. 0, P = 0.892; stage II: 3.0% vs. 3.2%, P = 0.861; stage III: 4.3% vs. 4.5%, P = 0.886)^[42].

In summary, there appears to be no significant difference in oncological aspects between NOSES and conventional laparoscopic surgery for the treatment of colorectal cancer. The percentage of tumor cells in peritoneal lavage fluid is more likely related to tumor stage than to surgical method. Performing NOSES in accordance with the consensus and standards does not increase the incidence of peritoneal infection or implantation metastasis.

Discussion

The key data from all single-center and multi-center studies identified were summarized into a table (Table 2), including study size, patient characteristics, surgical approach, tumor stage, tumor location, and short- and long-term outcomes. More intuitive presentation of our research results to help readers quickly discover what is needed and compare across different studies. In many respects, NOSES is significantly superior to conventional laparoscopic radical resection for colorectal cancer. For example, NOSES eliminates the need for an approximately 5 cm specimen extraction incision in the abdominal wall and related complications such as infection, hernia, and tumor implantation at the incision site. NOSES also reduces the incidence of perioperative complications, including ischemia, bleeding, intestinal obstruction, and anal function disorders. NOSES significantly improves postoperative pain control for patients, contributes to the rapid recovery of gastrointestinal function, shortens hospital stays, and conserves medical costs. In addition, it eliminates surgical scar formation, provides aesthetically pleasing outcomes, reduces anxiety associated with scarring, and improves the postoperative quality of life of patients. While significantly improving short-term outcomes, NOSES also has clear advantages in long-term outcomes. Indeed, previous studies have shown that the overall survival and 3 and 5-year disease-free survival rates of NOSES patients are comparable to those of patients undergoing conventional laparoscopy. NOSES patients often have a greater quality of life than conventional laparoscopic surgery patients do. Moreover, an increasing number of studies have confirmed that NOSES does not affect patients’ anal function, urinary function, or sexual function.

However, attention should be given to the inherent shortcomings and potential risks of NOSES for colorectal cancer, such as the issue of operative time. In recent years, some studies have suggested that there is no significant difference in operative time between NOSES and conventional laparoscopic surgery^[26,32]. Surgeons are recommended to become proficient in the NOSES procedure. The surgical team should have ample experience in laparoscopic surgery and be able to quickly and accurately complete digestive tract reconstruction under laparoscopy. Owing to its unique intra-abdominal anastomosis and specimen extraction methods, NOSES for colorectal cancer has potential bacteriological and oncological risks, such as bacterial positivity in abdominal lavage fluid, abdominal bacterial infection, positive tumor cells in abdominal lavage fluid, intra-abdominal exposure of tumor tissues, and shedding and implantation metastasis of tumor cells. Although performing NOSES surgery according to consensus guidelines will not increase the incidence of bacterial infection or tumor implantation^[4,59], concerns about bacteriological and oncological issues in NOSES will continue owing to the inherent shortcomings of this procedure, thus requiring surgeons to remain vigilant throughout the operation.

In recent years, transnatural orifice specimen extraction, an emerging minimally invasive surgical technique, has become a research hotspot in the field of surgery worldwide. The combination of robotics and NOSES is expected to further the development of colorectal tumor NOSES. This technology has been used in gastrointestinal surgery in multiple medical centers worldwide. As the number of cases of NOSES and relevant studies increase, NOSES is gradually becoming a standard treatment for colorectal tumors. It not only provides better treatment options for patients and doctors but also has attracted increasing attention and recognition from experts and scholars worldwide. NOSES is a better choice than conventional laparoscopic surgery for colorectal cancer when safety and patient suitability are guaranteed.

In contrast, despite the large number of NOSES performed in clinical practice, current research on colorectal tumor NOSES continues to consist of single-center, small-sample, retrospective analyses. Future studies should involve larger sample sizes, multicenter prospective studies, and randomized controlled trials to increase the strength of evidence and provide a more accurate assessment of the short- and long-term benefits of NOSES for patients undergoing radical resection for colorectal cancer. With clinical research as the goal, indications can be expanded to patients with locally advanced tumors, multiple primary colorectal cancers, and multiorgan resection. However, there is little evidence to support the use of NOSES in these patients, so NOSES in these patients is recommended to be performed only by experienced surgeons. Additionally, assessments of the postoperative quality of life and cosmetic results of NOSES for colorectal tumors still need to be standardized, and the choice of specimen retrieval routes through the anus or vagina requires further exploration to establish more specific and reasonable indications.

Conclusion

The literature indicates that NOSES for colorectal cancer is safe and feasible and has better outcomes in terms of short-term efficacy and long-term prognosis. In addition to satisfying the demand for the development of minimally invasive surgical methods, this technique also addresses the needs and interests of patients, and adopting it in clinical practice is worthy of consideration. We conclude that NOSES is ideal for patients who want to reduce abdominal incision scars, accelerate postoperative recovery, and relieve postoperative pain while ensuring good long-term oncological outcomes. Surgeons should fully grasp the indications of NOSES, adhere to unified surgical guidelines to perform the operations, and promote the standardized application of this procedure worldwide.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

National Key Research And Development Plan (2022YFC3401000), National Natural Science Foundation of China (92359302, 82472087), Guangdong Provincial Key Areas R&D Programs of “Precision medicine and stem cells”(2023B1111020005), the Natural Science Foundation for Outstanding Youth Team Project of Guangdong Province (2024B1515040030), Natural Science Foundation of Fujian Province (2024J011004), Fujian Provincial Health and Medical High Level Talent Team(XM050005).

Author contributions

X.H., R.W., Q.L. contributed to the conception and design of the study and analysis and interpretation of the data. X.H. participated in drafting and revising of the article for important intellectual content. W.H., P.L., X.Q. contributed to the conception and design of the study and provided final approval of the version to be submitted and any revised versions.

Conflicts of interest disclosure

There was no other potential conflict of interest to declare.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Weiling He.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

The data presented in this article are publicly available.