Anorectal dysfunction in patients with mid-low rectal cancer after surgery: A pilot study with threedimensional high-resolution manometry

lNTRODUCTlON

Colorectal cancer is one of the most common malignant tumors in the world. Rectal cancer, especially the mid-low type, in which the distal margin to the anal edge is ≤ 10 cm, is much more common in China[1]. Most patients treated by anterior resections suffer diverse problems related to abnormal defecation, such as frequent bowel movements, urgency, sensation of incomplete evacuation, and fecal incontinence, together referred to as anterior resection syndrome (ARS)[2]. The social activities, quality of life, and mental status of patients with ARS are seriously compromised[2].The efficacy of rectal irrigation, biofeedback, pelvic floor rehabilitation, and sacral nerve stimulation in patients with ARS has been examined but the number of studies and the respective sample sizes are small[3-5]. Therefore, the factors impacting anorectal function and its underlying mechanism remain to be adequately investigated.

Given the variable manifestations of ARS, “gold standard” diagnostic criteria are lacking[2]. Methods including anorectal manometry, transanal ultrasonography, and magnetic resonance imaging have been used to investigate the association between anorectal structure and function in anorectal organic diseases[6,7]. Three-dimensional high-resolution anorectal manometry (3D HR-ARM) uses miniaturized semiconductor sensors that surround a solid-state catheter and thus offers a novel means to serially measure the cross-section of the distal rectum and anal sphincter[8]. Using this solid catheter, the structural changes corresponding to anal sphincter function, including sphincter defects, can be detected. We therefore speculated that 3D HR-ARM could be used to evaluate anorectal structure and function in detail in patients who underwent anterior resection surgery.

The aim of this study was to evaluate anorectal function and to explore the structural factors associated with postoperative anorectal dysfunction in patients with mid-low rectal cancer, by following them from the time of diagnosis to 6 mo after anterior resection or a stoma reversal procedure.

MATERlALS AND METHODS

Patients

Patients diagnosed with mid-low rectal cancer at Peking Union Medical College Hospital from September 2012 to November 2013 who were older than 18 years of age were enrolled in this study, and the tumor distal margin to the anal edge was ≤ 10 cm, which was measured by the endoscopists during colonoscopic examination. Patients with a history of perianal diseases or surgery, intestinal diseases, or other diseases that might have affected intestinal or defecation function were excluded. All patients enrolled in the study underwent anterior resections (Dixon procedure or intersphincteric resection) with or without a temporary diverting stoma.

All procedures were performed in accordance with ethical standards of the Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the local Ethics Committee (S-482). All patients provided informed consent prior to enrollment in the study.

Questionnaires

ARS was evaluated in questionnaires completed by the patient with the face-to-face assistance of a welltrained investigator. The questions were designed to obtain general information, rectal cancer- and surgery-related information, and an assessment of defecation symptoms.

2.稅收可以促進企業盈利。一方面,企業為了增加雙贏,一方面是強大企業的生產能力,一方面為企業增加收入,另一方面,減少費用支出和稅收,如果他能夠完成稅收策劃和削減稅收,這將有助于保證企業盈利。

The low ARS (LARS) score has been validated in China and other countries and its reliability was consistently demonstrated[9-11]. With a total score of 42 points, it includes five items: (1) Frequency of uncontrolled intestinal flatus (

, gas incontinence; scores 0, 4, and 7 points); (2) fluid incontinence (0, 3,and 3 points); (3) bowel frequency (4, 2, 0, and 5 points); (4) clustering (0, 9, and 11 points); and (5)urgency (0, 11, and 16 points). The total LARS score ranges from no low LARS (0-20 points) to minor LARS (21-29 points) and major LARS (30-42 points). LARS score was assessed at 3 and 6 mo after the initial anterior resection or the stoma reversal procedure following a temporary diverting stoma, and both are referred as “after surgery” in the following text.

模型三為工具變量的回歸結果，結果表明，居民受教育程度對收入產生正向影響。此外，在加入控制變量和驅動變量及平方項后，城市居民的教育回報率為12.4%，農村居民的教育回報率為10.7%。這一回歸結果要比之前OLS估計結果高。為了進一步考察教育收益率在不同收入階層是否存在分化效應，本文也通過斷點回歸分析考察不同收入階層的教育收益率差異。

3D HR-ARM

Anorectal functions were evaluated using the ManoScan 3D HR-ARM system, which includes the ManoScan 360 A300 acquisition system, Manoview analysis software (version 2.2) (Sierra Scientific Instruments, Los Angeles, CA, United States), and solid-state electrodes (diameter 10.75 mm, length 6.4 cm, 256 data acquisition points) to generate a 3D pressure topographic profile of the anorectum. The solid-state electrodes connect with a balloon, and the balloon pressure is acquired with internal sensors within the acquisition module. 3D HR-ARM was performed preoperatively and 3-6 mo after surgery.

The patient was asked to evacuate his/her rectum at least 2 h before the measurement. The patient was placed in the left lateral position; after a digital rectal examination and informing about the anorectal manometry procedure, the electrode was placed. Then, the patient was told to keep calm and quiet for at least 2 min, during which time the resting pressure of the anus was recorded, and the mean value was calculated as the mean resting pressure. The length of high pressure zone of the anal sphincter is the length of the anal canal with mean resting pressure above 20 mmHg. The patient was then instructed to voluntarily squeeze the perianal muscles as hard as possible for at least 30 s three times separated by a 1-min rest. The average value was recorded as the maximal squeeze pressure of the anus. The perception of rectal filling and the capacity of the new rectum were measured by inflating a balloon with air in 10-mL increments. The thresholds of the patient's first perception of rectal filling,urgency to defecate, and maximal tolerable volume were assessed.

其中，Pi為單因子污染指數，Cis為重金屬濃度實測值，Cin為重金屬參比值，Eir為單因子危害系數，Tir為毒性響應系數。

Statistical analysis

All statistical analyses were performed using SPSS version 17 (SPSS Inc, Chicago, IL, United States).Numerical variables with a normal distribution are presented as the mean ± SD, and those with a nonnormal distribution as the median and interquartile range. Categorical variables are expressed as

(%).Fisher exact tests were used to assess between-group differences in categorical variables for the number of patients less than 40, and a Student’s

test or the Mann-Whitney

test was used to assess betweengroup differences in numerical variables with or without a normal distribution. A paired

-test was used to compare preoperative and postoperative anorectal functions evaluated by 3D HR-ARM, and McNemar-Bowker test or Wilcoxon signed-ranks test was used to compare the LARS scores between 3 and 6 mo after surgery. Pearson correlations or Spearman rank correlations were used to calculate the correlation coefficients. A

value ＜ 0.05 was considered statistically significant.

RESULTS

General data

Twenty-four patients with mid-low rectal cancer who fulfilled the inclusion criteria were enrolled in the study after providing informed written consent, including 14 males and 10 females, with an average age of 57.7 ± 10.4 years. Mid-rectal cancer was diagnosed in 14 and low rectal cancer in 10 patients. The cTNM stage and the major therapies are shown in Table 1. Twenty-two patients had the Dixon procedures, and two had the intersphincteric resections; among them, 18 patients had a temporary diverting stoma and a stoma reversal procedure.

Defecation symptoms

At 3 mo after surgery, 87.5% of patients (21/24) had LARS, and 83.3% (20/24) had major LARS. At 6 mo after surgery, 83.3% (20/24) still had LARS, and 58.3% (14/24) had major LARS (Table 2). There were significant differences in total LARS score and scores of four items except clustering between 3 mo and 6 mo after surgery (

＜ 0.05). There were no significant differences in LARS scores among patients with different sexes, ages, and tumor TNM stages.

A focal pressure defect in a 3D section of the anal canal was determined in 70.8% (17/24) of the patients postoperatively (Figure 1), including 15 (88.2%) who had received preoperative neoadjuvant therapy. The mean resting pressure of the anus in these 17 patients with focal pressure defects was 60.0± 27.9 mmHg. Patients with preoperative neoadjuvant therapy and a lower tumor location were more likely to have a focal pressure defect in a 3D section of the anal canal (

= 0.038,

= 0.019), but there were no significant correlations between the occurrence of focal pressure defects and sex, age, or tumor TNM stages (

＞ 0.05).

Perioperative anorectal function detected by 3D HR-ARM

The time from surgery to 3D HR-ARM examination was 117-178 d. There were no significant differences in anorectal function at the baseline between the surgery only group and the neoadjuvant therapy group(

＜ 0.05). Compared with the values before surgery, the length of the high-pressure zone of the anal sphincter after surgery was significantly shorter (

＜ 0.05), and the mean resting pressure and maximal squeeze pressure of the anus were significantly lower (

＜ 0.05) in all the patients, especially in the neoadjuvant therapy group after surgery. However, in the surgery only group, only the mean resting pressure was significantly lower (

＜ 0.05) postoperatively (Table 3). Because some patients could not cooperate well while inflating the balloon in the rectum, we list the number of patients who successfully acquired the first perception of rectal filling volume, urgency to defecate volume, and maximal tolerable volume after surgery in Table 3, and these data were not compared before and after surgery.

At both 3 mo and 6 mo after surgery, the tumor location (the tumor distal margin to the anal edge)were negatively correlated with LARS score (

= -0.499,

= 0.013;

= -0.584,

= 0.003) and urgency score (

= -0.444,

= 0.030;

= -0.425,

= 0.038). And at 6 mo after surgery, tumor location was negatively correlated with clustering score (

= -0.559,

= 0.005). Patients who received preoperative neoadjuvant therapy (chemoradiotherapy) had a higher uncontrolled intestinal flatus score (

= 5.614,

= 0.035) at 3 mo after surgery.

我自己是差點沒趕上此次克旗之行的。原因之一是因換購京A牌照的摩托車身份證被扣在車行。而按照這個年齡，似乎每一次出行的錯過，都必會在心底留有遺憾了。——在遙遠的匱乏單調年代里曾經那么向往的都市，其中充滿了文明、文化，擁有革命領導的工人階級的龐大隊伍，以及充滿了自我童年生活記憶的都市，怎么就一步步變成了隔一段時間就想盡快逃離的“現代牢獄”了呢？文明的擠壓與鈍化，不知不覺中就以強化的或懶惰的方式逼到你無法忍受，有能力、有機會、有條件、能湊起人數來去自主遠行、“反向融入”，融入到與原有向往完全相反的鄉村、田野、高原以及今日的草原，便是人生幸事。

Spastic peristaltic contractions from the new rectum to anus were detected in 45.8% (11/24) of the patients during 3D HR-ARM (Figure 2). The occurrence of spastic peristaltic contractions after surgery did not correlate significantly with sex, age, original tumor location, tumor TNM stages, or preoperative neoadjuvant therapy.

Correlation between anorectal dysfunction and symptoms

The postoperative mean resting pressure of the anus was negatively correlated with uncontrolled intestinal flatus score and uncontrolled fluid incontinence score (

= -0.507,

= 0.011;

= -0.472,

=0.020) at 3 mo after surgery. Both at 3 mo and 6 mo after surgery, the postoperative maximal squeeze pressure of the anus was negatively correlated with LARS score (

= -0.461,

= 0.023;

= -0.453,

=0.026) and clustering score (

= -0.405,

= 0.050;

= -0.539,

= 0.007). There were no significant correlations between the length of the high pressure zone of the anal sphincter, first perception of rectal filling volume, urgency to defecate volume, or maximal tolerable volume (for those cases with detected data)and LARS symptom scores.

Patients who had focal pressure defects in the anal canal and spastic peristaltic contractions from the new rectum to anus postoperatively had a higher LARS score than those without these dysfunctions at 3 mo after surgery [39 (2.0)

24 (23),

= 0.025; 39 (2.0)

39 (18.5),

= 0.017].

近年來，各醫學院校相繼開展機能實驗學整合。機能實驗學課程的開展，是醫學院校實驗教學改革的必然要求。該課程除了教師和學生兩大主體的參與，也離不開實驗技術人員。隨著學科建設不斷深入，機能實驗課程內容變得更加充實和復雜，對參與者提出了更高要求。實驗技術人員的工作水平從一定程度上反映了機能實驗中心的教學水平、科研水平和管理水平。但是，目前實驗技術人員的工作素養與實際工作缺乏有機結合，工作現狀亟待改善。

DlSCUSSlON

In this study, we found that LARS score decreased in the early phase after surgery over time, but 58.3%of patients still had major LARS at 6 mo after surgery. The mean resting pressure of the anus decreased in all patients after surgery, 70.8% of patients had focal pressure defects of the anal canal, and 45.8% had spastic peristaltic contractions from the new rectum to anus; these patients were more likely to have higher scores of LARS than patients without these dysfunctions at 3 mo after surgery.

ARS had been seen in up to 90% rectal cancer patients who received radical surgeries[2]. The LARS score is a widely validated score to evaluate ARS. It is simpler to use and better reflects the impact of ARS on the patient’s quality of life, enabling clinicians to rapidly assess postoperative bowel function[9-12]. A meta-analysis showed that the estimated prevalence of major LARS at 1 year and more after rectal radial resection was about 41%, and within 1 year after surgery the prevalence might be higher[13]. Our study found that major LARS was seen in more than half of the patients at 6 mo after surgery. Three years after surgery, 94.2% and 70.6% of patients who underwent coloanal anastomosis with low-lying rectal cancer still had moderate to severe incontinence and major LARS, respectively[12]. The impact of ARS on quality of life still persisted at 11.1 years (range, 7.1-16.1 years) after surgery[14].

Patients who had focal pressure defects in the anal canal had a higher uncontrolled intestinal flatus score (

= 7.309,

= 0.014), higher uncontrolled fluid incontinence score (

= 0.014), and higher urgency score (

= 7.034,

= 0.017) at 3 mo after surgery than those without focal pressure defects. Patients with focal pressure defects had a higher bowel frequency score and urgency score (

= 6.203,

= 0.019;

=5.905,

= 0.049) at 6 mo after surgery. Patients who had spastic peristaltic contractions postoperatively had a higher bowel frequency score (

= 6.375,

= 0.023;

= 6.044,

= 0.029) at both 3 mo and 6 mo after surgery.

2.2.1苗木類型蘋果苗木依砧木類型一般可分為喬化砧苗和矮砧苗，矮砧苗包括矮化中間砧苗和矮化自根苗，不同苗木立地條件的要求有差異，應根據果園土壤和氣候等條件選擇與之相適應的苗木類型。

(3)從分配率上看，大于0.045 mm粒級在底流中的總分配率(即粗粒正配率)為98.83%，沉淀效果較好。

（2）加強產品質量大數據建設的頂層設計和規劃。產品質量大數據發展存在問題的重要原因是頂層設計和規劃不到位、不完善。加快產品質量大數據建設，要系統規劃，統籌協調，按照量力而行、適度超前的原則，科學規劃產品質量大數據、云計算、人工智能的技術路線和發展路徑，適時出臺產品質量大數據建設規劃。要加快制度的“廢改立”，破除產品質量大數據深度利用、綜合利用的政策藩籬，形成目標協同、層次明確、銜接嚴密的大數據發展政策體系。要堅持問題導向、突出應用，科學規劃產品質量大數據建設的重點任務、時間節點，優化數據中心布局，促進大數據與實體經濟的深度融合，充分發揮質量大數據的作用。

Currently, there have been no “gold standard” objective methods to evaluate the anorectal function.Anorectal manometry has been widely used to evaluate anorectal function in patients with defecation dysfunction and fecal incontinence, and 3D HR-ARM has been confirmed to be superior in detecting sphincter dysfunction to traditional linear ARM and HR-ARM[8]. In this study, with 3D HR-ARM we not only found a decreased mean resting pressure of the anus in all patients, but also worse parameters of anorectal manometry in patients with preoperative neoadjuvant therapy after surgery. These results are consistent with the mainstream view that preoperative neoadjuvant radiotherapy is a risk factor for postoperative bowel dysfunction[17]. It had been found that the new rectum of patients with preoperative neoadjuvant therapy was less sensitive to mechanical and temperature stimulation than that of patients who underwent direct surgery[18], even though there was evidence that the short term benefits of neoadjuvant treatment including tumor control, downstaging, improved bowel symptoms,and increased length of the high-pressure zone of the anal sphincter were demonstrated in patients with mid-low rectal cancer 6 wk after adjuvant radiotherapy[19,20].

教材中安排了學生自己動手來完成青霉和匍枝根霉的培養和觀察，使學生掌握真菌的主要特征。然而，在課堂教學實踐中，學生按照教材的操作提示能看到饅頭和橘皮發霉，但由于混有雜菌，學生難以觀察到典型的青霉和匍枝根霉的形態結構。且青霉分生孢子梗上成串的孢子容易碰落，菌絲容易斷裂，蓋蓋玻片時要特別小心，既緩慢又不能移動位置，給教學帶來了一定的難度。本文嘗試制作青霉與匍枝根霉模型，可以讓學生觀察到清晰、完整的青霉和匍枝根霉的形態，不僅能很好地詮釋教學難點，還能提高學生的學習興趣。

Decreased anal mean resting pressure had been demonstrated to be involved in the pathophysiological mechanism of ARS[2,16], but anal mean resting pressure was not precise enough to reflect the anal pressure distribution. In this study, the mean resting pressure in patients with focal pressure defects in the anus was comparable with that previously measured in 110 healthy Chinese volunteers[8], and the pressure of the anal canal was more uneven after than before surgery according to the 3D profiles. Therefore, 3D HR-ARM might reveal more details in ARS patients, even though there was controversy over whether 3D HR-ARM could replace 3D ultrasonography in detecting anal sphincter defects[7]. Considering that patients who had fecal incontinence were more likely to have focal pressure defects in the anal canal compared to constipation patients or healthy people[23], and in this study patients detected with focal pressure defects had higher scores of LARS, uncontrolled intestinal flatus,uncontrolled fluid incontinence, and urgency at 3 mo and higher scores of bowel frequency and urgency at 6 mo after surgery than those without, we speculate that focal pressure defects are involved in pathophysiological changes of LARS, especially for incontinence and urgency in ARS patients.

Studies focused on the motility of the new rectum were rare, except that Emmertsen

[24] reported a significantly higher postprandial response of the rectum and neorectal pressure in LARS patients.Interestingly, in this study we captured spastic peristaltic contractions from the new rectum to anus by3D HR-ARM in nearly half of the patients after surgery, which were related to higher bowel frequency score and higher LARS score. This indicates that the new rectum still preserves the spastic peristaltic contractions of the sigmoid colon, which results in frequent bowel movements and even clustering defecation. We gained enlightenment from this result to teach the patients to start the training exercise of the new rectum for storage and sensation as early as possible after surgery, which could be helpful to alleviate their frequent bowel movements.

The limitations of this pilot study were the small sample size and the short follow-up duration.Considering the discomfort of patients, we performed the 3D HR-ARM once during 3-6 mo after surgery. After this study, the patients entered into the routine follow-up and individualized therapy for the LARS symptoms. In this study, we did not collect the data of sexual practices and anal sex practices and did not include patients with upper rectal cancer, because it is considered that anterior resection for those patients less affects the anorectal function.

Except preoperative adjuvant radiotherapy, tumor location was another important risk factor for LARS[13,21]. We found that patients with a lower tumor location had a higher LARS score, and that tumor location was related to the presence of focal pressure defects in the anal canal. Additionally,Battersby

[22] first developed a Pre-Operative LARS score to predict bowel dysfunction severity prior to anterior resection, and the key predictive factors for LARS were age (at surgery), tumor height,total

partial mesorectal excision, stoma, and preoperative radiotherapy.

CONCLUSlON

In this pilot prospective study, we found that more than half of the patients with mid-low rectal cancer have major LARS at 6 mo after surgery, the mean resting pressure of the anus decreases in all patients,and the anorectal dysfunctions, especially anal focal pressure defects and spastic peristaltic contractions from the new rectum to anus, have correlations with LARS scores after surgery. The anal focal pressure defects and spastic peristaltic contractions from the new rectum to anus might be the major pathophysiological mechanisms of LARS. Further studies are needed to validate our findings regarding LARS and explore effective interventions based on the pathophysiology.

ARTlCLE HlGHLlGHTS

Research conclusions

Anorectal function worsens after surgery in mid-low rectal cancer patients. The focal pressure defects of anal canal and spastic peristaltic contractions from the new rectum to anus postoperatively might be involved in the pathophysiological mechanisms of LARS.

Research perspectives

More studies need to be done to confirm our finding that the anal focal pressure defects and spastic peristaltic contractions from the new rectum to anus might be involved in the pathophysiological mechanisms of LARS, and effective interventions should be explored to alleviate the suffering of rectal cancer patients after surgery.

ACKNOWLEDGEMENTS

The authors thank Dr. Tao Χu at the Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, China for assistance with the statistical analyses. The abstract was presented as a poster at the joint 2017 meeting of the Asian Neurogastroenterology and Motility Association (ANMA)and the Japanese Society of Neurogastroenterology and Motility (JSNM) held in Osaka, Japan March 23-25, 2017.

FOOTNOTES

Fang ΧC and Χiao Y were the guarantors and designed the study, enrolled and followed the patients, and critically revised the manuscript; Pi YN collected and analyzed the data and wrote the manuscript;Wang ZF participated in manometry and data interpretation; Lin GL and Qiu HZ enrolled and followed the patients;all authors reviewed the final version of this manuscript and agreed to its submission.

the National High-tech R & D Program (“863” Program) of China, No. 2010AA023007.

還有的是一音素結構有多種讀法的問題，例如‘ou’ ，它有多至六到七個讀法，我卻未見過有phonics課程教/au/以外的讀音。這里讓大家看看:

The study was reviewed and approved by the Science and Research Office of Peking Union Medical College Hospital (Beijing).

All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

There are no conflicts of interest to report.

后來，他又做了幾件讓人哭笑不得的調皮事，其中一件震驚了整個幼兒園。你知道為什么嗎？小烏龜啊，真的是一個小傻瓜。他在幼兒園結交了一個好吃懶做的壞朋友大黑貓。大黑貓心眼壞，他想吃掉小烏龜，可是小烏龜有防身的鎧甲。遇到危險的時候，小烏龜會躲到殼里一動不動，殼就是小烏龜的家，非常安全。大黑貓就想出一個壞點子，他不僅想吃掉小烏龜，還要吃烤熟的烏龜肉呢。

Data can be acquired from the corresponding author at fangxiucai2@aliyun.com.

The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Yan-Na Pi 0000-0001-8630-8185; Yi Χiao 0000-0002-4309-1227; Zhi-Feng Wang 0000-0001-6347-4404;Guo-Le Lin 0000-0001-6225-3028; Hui-Zhong Qiu 0000-0002-5991-5227; Χiu-Cai Fang 0000-0002-5600-8779.

Chen YL

雅斯貝爾斯曾說：“教育本身就意味著：一棵樹搖動另一棵樹，一朵云推動另一朵云，一個靈魂喚醒另一個靈魂。”教師在一字一句的品讀中洋溢出來的激情，在一筆一畫的書寫中表現出的專注，在細致入微的講解中透露出的執著，都對孩子起到了潛移默化的作用。

Wang TQ

使用基于服務架構的監測預警系統具有較好的靈活性、通用性及可擴展性，同時利用PUSH技術，“主動”將預警信息推送，使防汛工作人員能夠隨時隨地靈活地掌握各類重要的防汛防旱預警信息，極大提高了防汛防旱搶險救災應急指揮能力。目前，本系統主要對水情、雨情進行實時監測預警，將來旱情預警、工情預警以及防汛啟動條件預案可以分別對相應的基礎數據與警戒值進行比較，對超出警戒范圍的要素進行預警，具有極強的可擴展性。

Chen YL

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