Neoadjuvant treatment of colorectal cancer: comprehensive review.

BACKGROUND: Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery. METHODS: A narrative review of the most recent relevant literature was conducted. RESULTS: Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients. CONCLUSION: Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments.

Tailored Pre-Operative Antibiotic Prophylaxis to Prevent Post-Operative Surgical Site Infections in General Surgery.

The average American today undergoes three inpatient and two outpatient surgical procedures during one's life, each of which carries with it a risk of post-operative infection. It has long been known that post-operative infections cause significant morbidity in the immediate peri-operative period, but recent evidence suggests that they can have long-term consequences as well, increasing a patient's risk of infectious complications in unrelated surgeries performed months or even years later. While there are several theories on the origin of this association, including bacterial colonization of a post-operative infectious wound site, antimicrobial resistance from curative courses of antibiotics, subclinical immunosuppression, or the creation of an inflammatory "pathobiome" following an infectious insult, it is ultimately still unclear why patients who experience a single post-operative infection seem to be at a significantly higher risk of experiencing subsequent ones. Regardless, this association has significant implications for the routine use of pre-operative antibiotic prophylaxis. Indeed, while the prescription of antibiotics pre-operatively has dramatically reduced the rate of post-operative infections, the chosen prophylaxis regimens are typically standardized according to national guidelines, are facing increasing antimicrobial resistance patterns, and have been unable to reduce the risk of post-operative infection to acceptably low levels for certain surgeries. As a result, some clinicians have speculated that tailoring pre-operative antibiotic prophylaxis according to a patient's prior infectious and operative history could improve efficacy and further reduce the rate of post-operative infections. The purpose of this review is to describe the evidence for the link between multiple post-operative infections and explore the efficacy of individualized pre-operative prophylaxis.

Western Diet-induced Transcriptional Changes in Anastomotic Tissue Is Associated With Early Local Recurrence in a Mouse Model of Colorectal Surgery.

OBJECTIVE: To determine the timeframe and associated changes in the microenvironment that promote the development of a diet-induced local-regional recurrence in a mouse model of colorectal surgery. BACKGROUND: Postoperative recurrence and metastasis occur in up to 30% of patients undergoing attempted resection for colorectal cancer (CRC). The underlying mechanisms that drive the development of postoperative recurrences are poorly understood. Preclinical studies have demonstrated a diet and microbial-driven pathogenesis of local-regional recurrence, yet the precise mechanisms remain undefined. METHODS: BALB/C mice were fed a western diet (WD) or standard diet (SD), underwent a colon resection and anastomosis, given an Enterococcus faecalis enema on postoperative day (POD) 1, and subjected to a CT26 cancer cell enema (mimicking shed cancer cells) on POD2. Mice were sacrificed between POD3 and POD7 and cancer cell migration was tracked. Dynamic changes in gene expression of anastomotic tissue that were associated with cancer cell migration was assessed. RESULTS: Tumor cells were identified in mice fed either a SD or WD in both anastomotic and lymphatic tissue as early as on POD3. Histology demonstrated that these tumor cells were viable and replicating. In WD-fed mice, the number of tumor cells increased over the early perioperative period and was significantly higher than in mice fed a SD. Microarray analysis of anastomotic tissue found that WD-fed mice had 11 dysregulated genes associated with tumorigenesis. CONCLUSIONS: A WD promotes cancer cells to permeate a healing anastomosis and migrate into anastomotic and lymphatic tissue forming viable tumor nodules. These data offer a novel recurrence pathogenesis by which the intestinal microenvironment promotes a CRC local-regional recurrence.

Role of the Microbiome in Malignancy.

The conceptual underpinning of carcinogenesis has been strongly influenced by an expanded understanding of the human microbiome. Malignancy risks in diverse organs have been uniquely tied to aspects of the resident microbiota in different organs and systems including the colon, lungs, pancreas, ovaries, uterine cervix, and stomach; other organs are increasingly linked to maladaptive aspects of the microbiome as well. In this way, the maladaptive microbiome may be termed an oncobiome. Microbe-driven inflammation, anti-inflammation, and mucosal protection failure, as well as diet-induced microbiome derangement are all mechanisms that influence malignancy risk. Therefore, they also offer potential avenues of diagnostic and therapeutic intervention to modify malignancy risk, and to perhaps interrupt progression toward cancer in different sites. Each of these mechanisms will be explored using colorectal malignancy as a prototype condition to demonstrate the microbiome's role in carcinogenesis.

Clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons.

The American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) are dedicated to ensuring high-quality innovative patient care for surgical patients by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus as well as minimally invasive surgery. The ASCRS and SAGES society members involved in the creation of these guidelines were chosen because they have demonstrated expertise in the specialty of colon and rectal surgery and enhanced recovery. This consensus document was created to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus and develop clinical practice guidelines based on the best available evidence. While not proscriptive, these guidelines provide information on which decisions can be made and do not dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, healthcare workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. These guidelines should not be deemed inclusive of all proper methods of care nor exclusive of methods of care reasonably directed toward obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all the circumstances presented by the individual patient. This clinical practice guideline represents a collaborative effort between the American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and was approved by both societies.

Simple Diverting Colostomy for Sacral Pressure Ulcers: Not So Simple After All.

BACKGROUND: Surgeons are often asked to provide a diverting colostomy to enable healing or simplify management of sacral pressure ulcers. However, little evidence exists regarding the safety of a diversion in this often compromised patient population. We hypothesized that malnourished patients with sacral pressure ulcers have poor outcomes with fecal diversion. METHODS: ACS-NSQIP (2012-2018) was used to identify patients who underwent elective diverting colostomy for sacral pressure ulcers. Demographics, comorbidities, and perioperative details were recorded. Postoperative complications and 30-day mortality were compared between patients with moderate/severe hypoalbuminemia (< 2.5 g/dL) vs those with albumin > 2.5 g/dL. RESULTS: We identified a total of 863 patients who underwent elective diverting colostomy for sacral pressure ulcer. Mean age was 57.5 years old. Rate of associated comorbidities was high, with most patients classified as ASA class 3 or 4. Over 40% of patients had a preoperative albumin level < 2.5 g/dL. Thirty-day overall postoperative mortality was 6.7%. This was significantly higher in patients with hypoalbuminemia (11.4% vs. 3.5%, p < 0.001). On multivariable regression analysis, preoperative albumin < 2.5 g/dL was independently associated with mortality (OR 1.92, p = 0.039). Other factors associated with mortality included increased age (OR 1.04 per year, p < 0.001), preoperative sepsis (OR 1.66, p = 0.003), and Black race (OR 2.2, p = 0.01). CONCLUSIONS: Diverting colostomy performed for patients with sacral pressure ulcers is associated with a substantial risk of postoperative death. Surgeons should carefully consider risks of diversion in this patient population, especially in malnourished patients with hypoalbuminemia.

Intra-operative Radiation Therapy for Colorectal or Anal Cancer at Risk for Margin-Positive Resection: Initial Results of a Single-Institution Registry.

PURPOSE: Pelvic recurrence of rectal or anal cancers is associated with considerable morbidity and mortality. We report our initial experience with an aggressive intra-operative radiotherapy (IORT) program. METHODS: Patients with locally advanced or recurrent rectal or anal cancers considered to have a high likelihood of R1 or R2 resection after multi-disciplinary review underwent surgical excision and IORT using a high-dose-rate afterloader (Ir-192) and HAM applicator. Endpoints included local or distant recurrence, and acute and late toxicity graded using the American College of Surgeons (ACS) NSQIP and the LENT-SOMA scale. RESULTS: Twenty-one patients, largely with prior history of both pelvic external beam radiotherapy (EBRT, median 50.4 Gy) and surgical resection, underwent excision with IORT (median dose 12.5 Gy, range 10-15). Median follow-up was 20 months. Twelve (57%) patients had failure at the IORT site. Freedom from failure (FFF) within the IORT field was associated with resection status (FFF at 1 year 75% for R0 vs 15% for R1/2, p = 0.0065) but not re-irradiation EBRT or IORT dose (p > 0.05). Twelve, 5, and 13 patients experienced local, regional, and distant failure, respectively; 3 (14%) patients were disease-free at last follow-up. The most frequent acute toxicity was sepsis/abscess (24%). One patient (5%) required a ureteral stent; no patients developed neuropathy attributable to IORT. CONCLUSIONS: In patients treated with excision and IORT for locally recurrent cancer, R0 resection is a critical determinant of local control. For patients with R1/2 resection, poor disease-free outcomes warrant consideration of a different treatment strategy.

The Science of Anastomotic Healing.

Intestinal anastomotic tissue follows a similar pattern of healing that is seen in all tissues with characteristic inflammatory, proliferative, and remodeling phases. Several aspects of intestinal healing are distinct from other tissues, however, including its time course and interaction with the environment of the gastrointestinal tract. As the anastomosis progresses through each stage, initial inflammatory cells are replaced by collagen-producing fibroblasts that generate the anastomosis' strength. A complex network of cell-to-cell signaling mediates this process through the release of cytokines and growth factors including platelet-derived growth factor (PDGF), transforming growth factor-ß (TGF-ß), and vascular endothelial growth factor (VEGF). Interventions based on these signaling pathways have been shown to improve anastomotic strength in animals, though methods for improving anastomotic healing in human patients remain unclear. Given the risks associated with anastomotic failure in patients, there is value in monitoring inflammatory markers and cytokines that can indicate the presence of a leak.

Is Previous Postoperative Infection an Independent Risk Factor for Postoperative Infection after Second Unrelated Abdominal Operation?

BACKGROUND: Infections after abdominal surgery remain a significant problem. Although preoperative antibiotic prophylaxis is a primary strategy used to reduce postoperative infections, it is typically prescribed based on standardized protocols, without attention to previous infection or antibiotic history. Patients with a previous infection after surgery may be at higher risk for infectious complications after subsequent operations owing to antibiotic resistance. We hypothesized that a previous postoperative infection is a significant risk factor for the development of infection after a second unrelated surgery. STUDY DESIGN: We performed a retrospective study of patients who had undergone 2 unrelated abdominal operations at a tertiary care center from 2012 to 2018. Clinical variables and microbiological culture results were abstracted. Univariate and multivariable regression models were constructed. RESULTS: Of 758 patients, 15.0% (n = 114) developed an infection after the first operation. After the second operation, 22.8% (n = 26) of those with a previous infection developed another infection, whereas the incidence of an infection after the second operation was only 9.5% (n = 61) in patients who did not develop an infection after the first operation. Multivariable analysis demonstrated that previous infection (odds ratio 2.49, 95% CI 1.46 to 4.25) was associated with future infection risk. Microbiological analysis found that infections after the second surgery were significantly more likely to be antibiotic resistant than infections after the first surgery (82.3% vs 64.1%; p = 0.036). Strikingly, 49% of infections after the second surgery were resistant to the antibiotic prophylaxis given at the time of incision. CONCLUSIONS: Previous postoperative infection is an independent risk factor for a subsequent postoperative infection and is associated with resistance to standard prophylaxis. Individualization of antibiotic prophylaxis in patients with a previous postoperative infection is warranted.

Enterococcus faecalis promotes a migratory and invasive phenotype in colon cancer cells.

Much about the role of intestinal microbes at the site of colon cancer development and tumor progression following curative resection remains to be understood. We have recently shown that collagenolytic bacteria such as Enterococcus faecalis predominate within the colon postoperatively, particularly at the site of the colon reconnection (i.e. anastomosis) in the early period of post-surgical recovery. The presence of collagenolytic bacteria at this site correlates with the tumor progression in a mouse model of post-surgical tumor development. In the present study we hypothesized, that collagenolytic bacteria, such as E. faecalis, play an important yet to be discovered role in tumor formation and progression. Therefore the aims of this study were to assess the role of collagenolytic E. faecalis on the migration and invasion of a murine colon cancer cell line. Results demonstrated that both migration and invasion were induced by E. faecalis with collagenolytic activity being required for only invasion. Bidirectional signaling in the E. faecalis-cancer cell interaction was observed by the discovering that the expression of gelE in E. faecalis, the gene required for collagenase production, is expressed in response to exposure to CT26 cells. The mechanism by which migration enhancement via E. faecalis occurs appears to be dependent on its ability to activate pro-uPA, a key element of the urokinase-plasminogen system, a pathway that is well - known to be important in cancer cell invasion and migration. Finally, we demonstrated that collagenase producing microbes preferentially colonize human colon cancer specimens.

Histopathology of Colectomy Specimens Predicts Endoscopic Pouch Phenotype in Patients with Ulcerative Colitis.

BACKGROUND: The endoscopic appearance in patients with "pouchitis" after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can be quite heterogenous. Patients with an endoscopic phenotype resembling Crohn's disease (CD) are at high risk of pouch loss. AIMS: We aimed to assess how the histopathology of colectomy specimens predicts endoscopic pouch phenotypes in UC. METHODS: We retrospectively assessed pouchoscopies from patients with UC who underwent IPAA and classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥ 6 months from ileostomy takedown. We assessed the clinical and pathological data including deep, focal inflammation, granulomas, and terminal ileal involvement in the colectomy specimens. Logistic regression analysis was performed to identify contributing factors to each phenotype. RESULTS: This study included 1,203 pouchoscopies from 382 patients with UC. On multivariable analysis, deep inflammation was significantly associated with pouch fistulas (Odds ratio 3.27; 95% confidence interval 1.65-6.47; P = 0.0007). Of the 75 patients with deep inflammation, only two patients (2.7%) were diagnosed with CD based on pathology review. Terminal ileal involvement significantly increased the risk of afferent limb involvement (Odds ratio 2.96; 95% confidence interval 1.04-8.47; P = 0.04). There were no significant associations between other microscopic features and phenotypes. CONCLUSIONS: We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.

Outcomes of Ileoanal Pouch Anastomosis in Pediatric Ulcerative Colitis Are Worse in the Modern Era: A Time Trend Analysis Outcomes Following Ileal Pouch-Anal Anastomosis in Pediatric Ulcerative Colitis.

BACKGROUND: Despite significant differences in surgical outcomes between pediatric and adult patients with ulcerative colitis (UC) undergoing colectomy, counseling on pediatric outcomes has largely been guided by data from adults. We compared differences in pouch survival between pediatric and adult patients who underwent total proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: This was a retrospective single-center study of patients with UC treated with IPAA who subsequently underwent pouchoscopy between 1980 and 2019. Data were collected via electronic medical records. We stratified the study population based on age at IPAA. Differences between groups were assessed using t tests and chi-square tests. Kaplan-Meier curves were used to compare survival probabilities. Differences between groups were assessed using a log-rank test. RESULTS: We identified 53 patients with UC who underwent IPAA before 19 years of age and 329 patients with UC who underwent IPAA at or after 19 years of age. Subjects who underwent IPAA as children were more likely to require anti-tumor nerosis factor (TNF) postcolectomy compared with adults (41.5% vs 25.8%; P < .05). Kaplan-Meier estimates revealed that pediatric patients who underwent IPAA in the last 10 years had a 5-year pouch survival probability that was 28% lower than that of those who underwent surgery in the 1990s or 2000s (72% vs 100%; P < .001). Further, children who underwent IPAA and received anti-TNF therapies precolectomy had the most rapid progression to pouch failure when compared with anti-TNF-naive children and with adults who were either exposed or naive precolectomy (P < .05). CONCLUSIONS: There are lower rates of pouch survival for children with UC who underwent IPAA following the uptake of anti-TNF therapy compared with both historical pediatric control subjects and contemporary adults.

Ileal pouch­anal anastomosis is the most common surgical approach for patients with ulcerative colitis undergoing total proctocolectomy. Outcomes are informed by heterogeneous adult data cohorts often predating anti-tumor necrosis factor uptake. We find that for children in the modern era pouch loss occurs at higher rates.

Endoscopic Phenotype of the J Pouch in Patients With Inflammatory Bowel Disease: A New Classification for Pouch Outcomes.

BACKGROUND & AIMS: Pouchitis is a common complication of ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis who have undergone colectomy. Pouchitis has been considered a single entity despite a broad array of clinical and endoscopic patterns. We developed a novel classification system based on the pattern of inflammation observed in pouches and evaluated the contributing factors and prognosis of each phenotype. METHODS: We identified 426 patients (384 with ulcerative colitis) treated with proctocolectomy and IPAA who subsequently underwent pouchoscopies at the University of Chicago between June 1997 and December 2019. We retrospectively reviewed 1359 pouchoscopies and classified them into 7 main pouch phenotypes: (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted 6 months after ileostomy takedown. Logistic regression analysis was used to assess factors contributing to each phenotype. Pouch survival was estimated by the log-rank test and the Cox proportional hazards model. RESULTS: Significant contributing factors for afferent limb involvement were a body mass index of 25 or higher and hand-sewn anastomosis, for inlet involvement the significant contributing factor was male sex; for diffuse inflammation the significant contributing factors were extensive colitis and preoperative use of anti-tumor necrosis factor drugs, for cuffitis the significant contributing factors were stapled anastomosis and preoperative Clostridioides difficile infection. Inlet stenosis, diffuse inflammation, and cuffitis significantly increased the risk of pouch excision. Diffuse inflammation was associated independently with pouch excision (hazard ratio, 2.69; 95% CI, 1.34-5.41; P = .005). CONCLUSIONS: We describe 7 unique IPAA phenotypes with different contributing factors and outcomes, and propose a new classification system for pouch management and future interventional studies.

Management of colorectal cancer during the COVID-19 pandemic: Recommendations from a statewide multidisciplinary cancer collaborative.

COVID-19 has resulted in significant disruptions in cancer care. The Illinois Cancer Collaborative (ILCC), a statewide multidisciplinary cancer collaborative, has developed expert recommendations for triage and management of colorectal cancer when disruptions occur in usual care. Such recommendations would be applicable to future outbreaks of COVID-19 or other large-scale disruptions in cancer care.

Enterococcus faecalis Is Associated with Anastomotic Leak in Patients Undergoing Colorectal Surgery.

Background: Anastomotic leak is among the most dreaded complications in patients undergoing colorectal surgery. We have discovered that in rodents, collagenase-producing bacteria, particularly Enterococcus faecalis, promotes anastomotic leak by degrading healing anastomotic tissue. Yet, it is unclear if these organisms play a role in humans. Patients and Methods: Patients undergoing colorectal resection at the University of Chicago from July 2014 through June 2019 who developed a post-operative infection were stratified into infections that resulted from an anastomotic leak, a Hartmann pouch stump leak, or a deep infection without an associated staple line leak. Results: Forty-two patients had available culture data. Of these patients, 19 were found to have an anastomotic leak, 7 had a stump leak, and 16 had a deep infection that was not associated with a staple line. Enterococcus faecalis was identified in 24% of all infections and was associated with the development of anastomotic leak (p = 0.029). When the organisms were classified into their known ability to produce collagenase, 74% of patients with an anastomotic leak were colonized with collagenase-producing organisms, compared with only 28% of patients with a deep infection or stump leak (p = 0.022). Antibiotic-resistant organisms were more common in patients with anastomotic leak (p = 0.01). Conclusions: Collagenase-producing and antibiotic-resistant organisms are more prevalent in anastomotic leak infections compared with other deep or organ/space infections. This lends evidence to a bacterial driven pathogenesis of leak and suggests that targeting these organisms may be a novel strategy to reduce this complication.

Combined mechanical and oral antibiotic bowel preparation is associated with prolonged recurrence-free survival following surgery for colorectal cancer.

BACKGROUND AND OBJECTIVES: Recent studies suggest that bacteria influence the pathogenesis of primary colorectal cancer (CRC), yet their role in recurrence after resection is largely unknown. We have discovered that collagenase-producing bacteria promote cancer recurrence in mice, and that antibiotic bowel decontamination decreases colonization of these same organisms in humans. We hypothesized that preoperative combined mechanical and oral antibiotic bowel preparation would improve disease-free survival (DFS) in patients undergoing surgery for CRC. METHODS: We reviewed a cancer registry of patients treated for CRC at a tertiary center. Patients who received bowel preparation were compared to those that did not via a 1:1-propensity score matched for follow-up, age, sex, BMI, stage, location, chemoradiation, infection, anastomotic leak, and blood transfusion. RESULTS: One thousand two hundred and seventy-nine patients met inclusion criteria. Following propensity score matching, 264 patients receiving bowel prep were matched to 264 patients who did not. Kaplan-Meier estimates showed that patients who received bowel prep had a significantly improved 5-year DFS compared to those that did not (76.3% vs. 64.2%; p < .01). Cox regression demonstrated that bowel prep was associated with improved DFS (HR, 0.57; 95% CI, 0.37-0.89; p < .01). CONCLUSION: Combined mechanical and oral antibiotic bowel preparation is independently associated with improved recurrence-free survival in patients undergoing surgery for CRC.