Essential updates 2020/2021: Colorectal diseases (benign)—Current topics in the surgical and medical treatment of benign colorectal diseases

Abstract The development of new drugs for inflammatory bowel disease (IBD) is remarkable, and treatment strategies using multiple agents and various techniques are required; however, the treatment strategy is likely to be complex. Therefore, appropriate evaluation of traditional surgical treatment strategies and accurate knowledge of the efficacy and limitations of novel treatments are required. Total infectious complications were found to be associated with the use of corticosteroids and anti‐tumor necrosis factor‐α agents, but not with immunomodulators, anti‐integrin agents, and 5‐aminosalicylic acid. Regarding surgical procedures for IBD, conceived anastomosis methods, including Kono‐S for Crohn's disease stenosis, are associated with better outcomes than conventional techniques. Autologous cell transplantation for Crohn's fistulae has been shown to have a favorable outcome. Diverticulitis is increasing and will be treated more frequently in the future. Risk factors for the incidence of diverticulitis and differences in pathogenesis according to right or left side diverticulitis have been reported. Antibiotic therapy may be omitted for uncomplicated diverticulitis. Moreover, regarding surgical procedures, both bowel resection and anastomosis are associated with favorable short‐term outcomes, higher stoma closure rate, and superior medical economy compared to Hartmann's procedure. Risk factors for recurrence after diverticulitis surgery may provide better postoperative follow‐up. In this review, we explore the current topics of colorectal benign diseases, focusing on IBD and diverticulitis, based on clinical trials and meta‐analyses from 2020‐2021. This review consolidates the available knowledge and improves the quality of surgical procedures and perioperative management for IBD and diverticulitis.


| INTRODUC TI ON
Inflammatory bowel disease (IBD) and diverticular disease are treated with a combination of medical and surgical therapy. The treatment and perioperative management of IBD and diverticulitis are major concerns among surgeons owing to the frequency and complexity of treatment and the severity of these diseases in clinical practice.
Currently, there are more than 1 million patients with IBD in the United States and 2.5 million in Europe, with substantial costs for health care. 1  cording to the Nationwide Inpatient Sample database. However, the majority of total proctocolectomies (69%) were performed within 24 hours of hospital admission. 2 The development of recent medical therapeutic agents for IBD has been remarkable; however, in many cases, surgical treatment is still required.
Diverticulitis and diverticular bleeding require medical treatment for colon diverticulosis. Moreover, diverticular disease-related mortality increased in 58 nations from 1994 to 2016; during this period, the relevant mortality rate increased in 57% of nations, whereas it decreased in only 7% Mortality associated with diverticular disease is increasing worldwide. 3 Surgical treatment for diverticulitis is likely to increase in the future.
Benign colorectal disease from 2018 to 2019 was reviewed in this journal. 4 Several clinical trials and meta-analyses have revealed novel treatment strategies and outcomes of these treatments developed in 2020. In the present review, newly determined characteristics, prognostic markers, non-operative management, and surgical treatment strategies optimal for IBD and diverticulitis are reviewed in accordance with articles published in the last 2 years (2020-2021) ( Figure 1).

| Association between IBD and other diseases
Arthritis, uveitis, pancreatitis, primary sclerosing cholangitis, and erythema nodosum are extraintestinal complications associated with IBD. Other diseases accompanying IBD have been reported in previous meta-analyses ( Table 1). Inflammatory resorption of alveolar bones is caused by polymicrobial biofilm-mediated disease.
Moreover, inflammatory processes are similar in periodontitis and IBD; the presence of periodontitis was associated with IBD, and periodontitis was strongly associated with both CD and UC. 5 The prevalence of cutaneous symptoms, pyoderma gangrenosum, psoriasis, and herpes zoster infection was frequently revealed to be accompanied by IBD. 6,7 Patients with IBD had an increased risk of with a high risk of HZ infection may benefit from an HZ vaccine. 8 Skin lesions are likely to be associated with IBD, and when treating patients with IBD, it is important to carefully examine the skin condition.
Anxiety and depression are commonly experienced by patients with IBD. The prevalence of corresponding symptoms was 32.1% and 25.2%, respectively, and the incidence of such was higher in patients with CD than in those with UC. 9 Moreover, these symptoms were associated with CD-related surgery, the Crohn's disease activity index, and corticosteroid use in patients with CD. 10 Patients with IBD often experience anxiety and depression during the perioperative period, and appropriate psychological care may be beneficial in these patients.

| Novel agents for IBD
The development of novel therapeutics for IBD is remarkable, so much so that it is difficult for general surgeons to understand all of them. The perioperative impact of these drugs will be discussed later; here, we enumerate novel therapeutic agents that were reported from 2020 to 2021. The results of the clinical trials are summarized in Table 2. Table S1 presents a summary of the approval status of novel agents.

Focus
Main results Reference

Periodontitis
The association between periodontitis and UC: present (OR 5.37) A meta-analysis showed that anti-TNFα agents prevented en- The safety and efficacy of fecal microbiota transplantation (FMT) for the treatment of Clostridioides difficile infections have been reported. 25 The intestinal flora plays an important role in the progression of UC. FMT has been shown to change the production of mucosal-associated invariant T cell cytokines. 26 In a metaanalysis, the safety and effectiveness of FMT for treating UC was reported. 27 Reportedly, FMT did not have a sustained effect on the treatment of UC patients unless the administration was repeated and prolonged. 28 The efficacy of FMT depends on microbial interactions between the donor and recipient strains. 29 The interactions between bacterial and metabolic pathways are also associated with the induction of remission. 30 Future studies are needed so that a sustained therapeutic effect can be obtained after FMT treatment in UC patients.

| Surgical management for IBD
In patients with CD, stenosis and fistula are the main indications for surgery. The optimal time for surgery and surgical procedures are the main concerns of surgeons ( those reported in a retrospective study (n = 134). 31 However, the incidence of relapse in patients with ileocolonic CD (n = 1863) after early bowel resection was compared to that after initial therapy, and the overall (OR: 0.53) and surgical relapse (OR: 0.47) were lower in patients who underwent early bowel resection than in those who received initial medical therapy. Moreover, the requirement for maintenance biologic therapy (OR: 0.24) was lower in patients who received early bowel resection than in those who received initial medical therapy. 32 The incidence of relapse after strictureplasty was also compared to that of bowel resection for patients with CD. The results demonstrated that strictureplasty alone increased disease recurrence compared to bowel resection (hazard ratio [HR]: 1.61), and the morbidity rate was not significantly different between the two groups. 33 Antimesenteric cutback end-to-end isoperistaltic anastomosis, known as Sasaki-W anastomosis, has been reported as a novel hand-sewn anastomotic technique for CD. 34 In a previous randomized control trial (RCT), Kono-S anastomosis, antimesenteric functional end-to-end handsewn anastomosis, were performed for the stenosis of the patients with CD, and the endoscopic recurrence was 22.2% in the Kono group and 62.8% in the conventional group (n = 79). 35 In a previous meta-analysis, the surgical outcomes of Kono-S were found to be 0% for surgical recurrence and 5% for endoscopic recurrence. 36 Kono-S anastomosis yields a favorable outcome with increasing evidence, hence may be considered an optimal procedure for CD stenosis. Additionally, the effects of the injection of autologous adipose tissue as a treatment modality for fistulas were reported in a cohort of CD patients in 2019. 38 Further trials on autologous tissue implantation have been attempted for fistulas in patients with CD in phase 1 trials and RCTs. Autologous subcutaneous, 39 adipose-derived, 40 and allogeneic mesenchymal stem cells, 41 as well as bone marrow-derived mesenchymal stromal cells, 42 were harvested in these trials, and the results suggested that such treatments for fistulas may be effective and feasible ( Ileal pouch-anal anastomosis (IPAA) was selected for patients who required total proctocolectomy. In recent years, the number of elderly patients undergoing the said procedures for UC has increased (age >50 years). The overall 30-day morbidity and mortality rates after surgery for elderly patients were 47.3% and 1.3%, respectively. Neither short-nor long-term functional outcomes were significantly different between patients aged 50-65 years and elderly patients (age >65 years). 48 However, the general condition, organ function, anorectal function, and activities of daily living (ADL) were impaired in the EOUC patients. 49 It is therefore important to select an appropriate procedure.
Proximal stoma diversion is commonly constructed when IPAA is performed. Anastomotic strictures and pouch failures have been shown to be more common in diverted patients than in nondiverted patients, but re-operation was more frequently required in non-diverted patients. However, this meta-analysis contained only one RCT; more evidence-based research is therefore desirable to exclude selection bias. 50 Retrospective studies showed that postoperative stoma outlet obstruction, a complication after stoma con- Ileal pouch-anal anastomosis is a safe procedure for EOUC patients; however, anorectal function and ADL should be considered when determining whether to perform the procedure. Further studies are needed to determine how to construct the diverting stoma.

| Perioperative managements for patients with IBD
Patients with IBD are often immunosuppressed before surgery, therefore requiring careful perioperative management.

TA B L E 5 (Continued)
In Crohn's disease, the treatment strategy emphasizes the preservation of intestinal function. Although Crohn's disease rarely leads to short bowel syndrome, some cases of this condition are unavoidable. 56 Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, has been approved in Japan for the treatment of short bowel syndrome.
Teduglutide promotes improved intestinal absorption function and reduces the need for long-term intravenous support, which is difficult to manage. 57 Pouchitis is a common complication after total proctocolec-

| Characteristic diverticulitis in a recent study
In the United States, the first incidence rate of diverticulitis was 2.9% between February 2015 and February 2020. The risk factors for the incidence of diverticulitis were being male, elderly (age >65 years), and Caucasian. 60   were not significantly different during antibiotic treatment and observation. 67 These results provide evidence for the omission of antibiotics in patients with uncomplicated acute diverticulitis.
In cases of recurrent diverticulitis or persistent symptoms, the choice between surgery and conservative treatment is an important concern. The failure rates of nonoperative management for acute diverticulitis with complicated abscesses is 16.4%, and the failure rates have not significantly decreased in the last 30 years. 68 The failure rate of percutaneous drainage as a nonoperative management for patients with pelvic abscess was three times higher than that for pericolic abscesses. 68,69 Hence, surgical treatment should be considered for abscesses in areas distant from colonic diverticulitis.
The aim of diverticulitis surgery is to treat acute inflammation and symptoms, and improve quality of life (QOL). A previous study compared elective sigmoid resection and conservative management in patients who had ongoing abdominal complaints for >3 months and/or frequently recurring left-sided diverticulitis of >2 episodes in 2 years.
The Gastrointestinal Quality of Life Index of the patients after sigmoid resection was higher than that after conservative treatment. 70 Colonic resection for recurrent diverticulitis improved QOL, and these data are helpful in determining the indications for bowel resection.

| Surgical procedure for diverticulitis
The major concerns of acute diverticulitis surgery are associated with bowel resection. These factors were analyzed in meta-analyses and RCTs (  74 Laparoscopic surgery is classified into two types; laparoscopic primary resection and laparoscopic lavage without primary resection. Laparoscopic peritoneal lavage is associated with higher morbidity than laparoscopic primary resection. 75 Immunosuppressed patients with diverticular disease have an increased risk of developing complicated diverticulitis. The mortality and morbidity rates of immunosuppressed patients were higher than those of immunocompetent patients for emergent surgery (RR: 1.91 and RR: 2.18, respectively), but not for elective surgery (RR: 1.70 and RR: 1.40, respectively). 76 Elective surgery may be planned for immunosuppressed patients with diverticulitis according to a meta-analysis.

| Recurrence after diverticulitis surgery
A time-to-event analysis for recurrence-and colostomy-free survival was performed using a large retrospective cohort. Of the patients with uncomplicated diverticulitis treated with non-operative methods, 19% underwent elective surgery and 81% were treated medically for recurrent uncomplicated diverticulitis after initial therapy.
Patients who underwent elective surgery were associated with lower rates of recurrence than those treated with medical therapy (15% vs 61% at 5 years, OR: 0.17). The rate of colostomy after elective surgery (1.8%) was lower than that after medical therapy (2.3%) at 5 years (OR: 2.3). 77 The recurrence rate of diverticulitis was reported to be 5.8% in a meta-analysis. Six factors related to recurrence after bowel resection with diverticulitis were identified: younger age and irritable bowel syndrome (preoperative); anastomotic level and uncomplicated recurrent diverticulitis (operative); absence of active diverticulitis on pathology and persistence of postoperative pain (postoperative). According to the results of this study, elective surgery prevents diverticulitis recurrence or colostomy risk. 78

| FUTURE PER S PEC TIVE AND SUMMARY
In this review, we present key articles on clinical trials and metaanalyses of IBD and diverticulitis from 2020 to 2021. The development of new drugs for IBD is remarkable, and treatment strategies using multiple agents and various techniques are required. It is necessary for surgeons to have a deep understanding of the surgical procedure and perioperative management, as well as the impact of new drugs. In terms of the surgical procedure for CD, it is important to select an optimal procedure that preserves bowel function, minimizes recurrence, and reduces complications.
The usefulness of autologous cell transplantation for fistulae on CD has been verified, and it may be clinically applied in the future. It is also important to enhance knowledge on perioperative management associated with IPAA in total proctocolectomy for IBD.
The incidence of diverticulitis is increasing, and more patients are expected to require surgical treatment in the future. According to recent reports, antimicrobial therapy is unnecessary for uncomplicated diverticulitis. Regarding surgical procedures for diverticulitis, both bowel resection and anastomosis are associated with favorable short-term outcomes, higher stoma closure rate, and more reasonable medical costs than HP. The risk factors for the recurrence of diverticulitis are summarized, and these data support the optimal management for postoperative diverticulitis patients. This review consolidates the available knowledge and improves the quality of surgical procedures and perioperative management in treating IBD and diverticulitis.

ACK N OWLED G EM ENTS
We would like to thank Editage (www.edita ge.com) for English language editing.

D I SCLOS U R E
Funding: No funding was received for this study.
Conflict of Interest: The authors declare no conflict of interest for this article.