Multi-omics machine learning to study host-microbiome interactions in early-onset colorectal cancer.

The incidence of early-onset colorectal cancer (eoCRC) is rising, and its pathogenesis is not completely understood. We hypothesized that machine learning utilizing paired tissue microbiome and plasma metabolome features could uncover distinct host-microbiome associations between eoCRC and average-onset CRC (aoCRC). Individuals with stages I-IV CRC (n = 64) were categorized as eoCRC (age ≤ 50, n = 20) or aoCRC (age ≥ 60, n = 44). Untargeted plasma metabolomics and 16S rRNA amplicon sequencing (microbiome analysis) of tumor tissue were performed. We fit DIABLO (Data Integration Analysis for Biomarker Discovery using Latent variable approaches for Omics studies) to construct a supervised machine-learning classifier using paired multi-omics (microbiome and metabolomics) data and identify associations unique to eoCRC. A differential association network analysis was also performed. Distinct clustering patterns emerged in multi-omic dimension reduction analysis. The metabolomics classifier achieved an AUC of 0.98, compared to AUC 0.61 for microbiome-based classifier. Circular correlation technique highlighted several key associations. Metabolites glycerol and pseudouridine (higher abundance in individuals with aoCRC) had negative correlations with Parasutterella, and Ruminococcaceae (higher abundance in individuals with eoCRC). Cholesterol and xylitol correlated negatively with Erysipelatoclostridium and Eubacterium, and showed a positive correlation with Acidovorax with higher abundance in individuals with eoCRC. Network analysis revealed different clustering patterns and associations for several metabolites e.g.: urea cycle metabolites and microbes such as Akkermansia. We show that multi-omics analysis can be utilized to study host-microbiome correlations in eoCRC and demonstrates promising biomarker potential of a metabolomics classifier. The distinct host-microbiome correlations for urea cycle in eoCRC may offer opportunities for therapeutic interventions.

Differences in Tumor-Associated T cell receptor repertoires between Early-Onset and Average-Onset colorectal cancer.

The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early onset CRC; EOCRC) has substantially increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020. EOCRC was defined as age < 50 years at diagnosis (N = 126), and AOCRC as age ≥ 60 years (N = 116). T cell receptor (TCR) abundance and clonality were measured by immunosequencing of tumors. Logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 EOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study. EOCRC tumors had significantly higher TCR diversity compared to AOCRC tumors in the discovery cohort (Odds Ratio (OR):0.44, 95% Confidence Interval (CI):0.32-0.61, p < .0001). This association was also observed in the replication cohort (OR : 0.74, 95% CI : 0.62-0.89, p = .0013). No significant differences in TCR abundance were observed between EOCRC and AOCRC in either cohort. Higher TCR diversity, suggesting a more diverse intratumoral T cell response, is more frequently observed in EOCRC than AOCRC. Further studies are warranted to investigate the role of T cell diversity and the adaptive immune response more broadly in the etiology and outcomes of EOCRC.

Close margin of adverse histologic factors with a negative primary tumor margin is not associated with increased locoregional recurrence in colon cancer.

PURPOSE: Locoregional recurrence after resection of colon cancer is increased when primary tumor margin is positive (<1 â€‹mm). Data is limited regarding the risk of locoregional recurrence with close margin (<1 â€‹mm) of histologic factors, such as intravascular tumor, intranodal tumor, tumor deposits, or extranodal extension. We hypothesized that close margin of these factors doesn't affect locoregional recurrence. METHODS: A retrospective review of all colon cancer surgical resections for adenocarcinoma from 2007 to 2020 was performed. Inclusion criteria were specimens with a negative primary tumor margin but a close margin of adverse histologic factors, defined as intravascular tumor, intranodal tumor, tumor deposits, or extranodal extension within 1 â€‹mm of a mesenteric or circumferential margin. RESULTS: Among 4435 pathology reports reviewed, 45 (1 â€‹%) of cases met inclusion criteria. Average follow-up was 38 months. The adverse histologic factor was identified as intranodal tumor in 24 (53 â€‹%) cases, intravascular tumor in 8 (17.8 â€‹%), tumor deposits in 5 (11.1 â€‹%), and more than one pathologic feature in 6 (13.3 â€‹%). There were 9 (20 â€‹%) recurrences; 6 (13 â€‹%) had distant recurrences only, 2 (4 â€‹%) patients had locoregional recurrences only, and 1 (2 â€‹%) patient had both locoregional and distant recurrence. The adverse histologic factor in these three patients was intravascular in two and both intravascular and intranodal in one. CONCLUSION: Based on our results, we do not have evidence that the presence of intravascular tumor, intranodal tumor, tumor deposits, or extranodal extension within 1 â€‹mm of a mesenteric or circumferential margin is associated with increased risk of locoregional recurrence.

Predictors of En Bloc, R0 Resection and Post-Procedural Complications Following Advanced Endoscopic Resections for Colorectal Neoplasms: Results of 1213 Procedures.

BACKGROUND: Advanced endoscopic resection techniques are used for treatment of colorectal neoplasms that are not amenable for conventional colonoscopic resection. Literature regarding the predictors of the outcomes of advanced endoscopic resections, especially from a colorectal surgical unit, is limited. OBJECTIVE: To determine the predictors of short- and long-term outcomes following advanced endoscopic resections. DESIGN: Retrospective case series. SETTINGS: Tertiary care center. PATIENTS: Patients who underwent advanced endoscopic resections for colorectal neoplasms from November 2011 to August 2022. INTERVENTION: Endoscopic mucosal resection, endoscopic submucosal dissection, hybrid endoscopic submucosal dissection, combined endoscopic laparoscopic surgery. MAIN OUTCOME MEASURES: Predictors of en bloc and R0 resection, bleeding, perforation was determined using univariable and multivariable logistic regression models. Cox regression models were used to determine the predictors of tumor recurrence. RESULTS: A total of 1213 colorectal lesions from 1047 patients were resected [median age 66 (58-72) years, 484 (46.2%) female, median body mass index 28.6 (24.8-32.6) kg/m 2]. Most neoplasms were in the proximal colon (898, 74%). Median lesion size was 30 (IQR: 20-40, range: 0-120) mm. 911 (75.1%) lesions had previous interventions. Most common Paris and Kudo classifications were 0-IIa flat elevation (444, 36.6%) and IIIs (301, 24.8%), respectively. En bloc and R0 resection rates were 56.6% and 54.3%, respectively. Smaller lesions, rectal location, and procedure type (endoscopic submucosal dissection) were associated with significantly higher en bloc and R0 resection rates. Bleeding and perforation rates were 5% and 6.6%, respectively. Increased age [1.06 (1.03-1.09), p < 0.0001] was a predictor for bleeding. Lesion size [1.02 (1.00-1.03), p = 0.03] was a predictor for perforation. Tumor recurrence rate was 6.6%. En bloc [HR 1.41 (95% CI 1.05-1.93), p = 0.02] and R0 resection [HR 1.49 (95% CI 1.11-2.06), p = 0.008] were associated with decreased recurrence risk. LIMITATIONS: Single center, retrospective study. CONCLUSIONS: Outcomes of advanced endoscopic resections can be predicted by patient and lesion-related characteristics. See Video Abstract.

Treatment of Microsatellite-Unstable Rectal Cancer in Sporadic and Hereditary Settings.

Microsatellite instability is rare in rectal cancer and associated with younger age of onset and Lynch syndrome. All rectal cancers should be tested for microsatellite instability prior to treatment decisions. Patients with microsatellite instability are relatively resistant to chemotherapy. However, recent small studies have shown dramatic response with neoadjuvant immunotherapy. Patients with Lynch syndrome have a hereditary predisposition to cancer and thus an elevated risk of metachronous cancer. Therefore, while "watch and wait" is a well-established practice for sporadic rectal cancers that obtain a complete clinical response after chemoradiation, its safety in patients with Lynch syndrome has not yet been defined. The extent of surgery for patients with Lynch syndrome and rectal cancer is controversial and there is significant debate as to the relative advantages of a segmental proctectomy with postoperative endoscopic surveillance versus a therapeutic and prophylactic total proctocolectomy. Surgical decision making for the patient with Lynch syndrome and rectal cancer is complex and demands a multidisciplinary approach, taking into account both patient- and tumor-specific factors. Neoadjuvant immunotherapy show great promise in the treatment of these patients, and further maturation of data from prospective trials will likely change the current treatment paradigm. Patients with Lynch syndrome and rectal cancer who do not undergo total proctocolectomy require yearly surveillance colonoscopies and should consider chemoprophylaxis with aspirin.

Acute colonic pseudo-obstruction: a retrospective review of the surgical outcomes.

PURPOSE: Limited data exist regarding the surgical outcomes of acute colonic pseudo-obstruction (ACPO), commonly referred to as Ogilvie syndrome, in modern clinical practice. The prevailing belief is that surgery should be avoided due to previously reported high mortality rates. We aimed to describe the surgical results of ACPO treated within our institution. METHODS: Our prospectively maintained colorectal surgery registry was queried for patients diagnosed with ACPO, who underwent surgery between 2009 and 2022. Postoperative complications were graded according to Clavien-Dindo (CD) classification. The primary outcome was postoperative mortality. RESULTS: A total of 32 patients who underwent surgery for ACPO were identified. Overall, nonoperative therapy was initially administered to 21 patients (65.6%). The surgeries performed included total abdominal colectomy (15, 43.1%), ascending colectomy with end ileostomy (8, 25%), transverse colostomy (5, 15.6%), ileostomy and transverse colostomy (3, 9.4%), and Hartmann's operation (1, 3.1%). Severe postoperative complications (CD grade 3 or 4) occurred in five patients (15.6%). No recurrence of ACPO was observed and no patient required reoperation. The average postoperative length of stay was 14.5 days, 30-day mortality was 6.3% (n = 2), and 90-day mortality was 15.6% (n = 5) due to complications of underlying comorbidities. CONCLUSIONS: Surgical treatment was effective for patients with ACPO refractory to medical therapy or presenting with acute complications. Although postoperative complications were frequent, both the 30- and 90-day mortality rates were lower than previously documented in the literature. Further investigations are warranted to determine the optimal surgical strategy, which may involve total or segmental colectomy, or diversion alone without resection.

Deep Transcriptomics Reveals Cell-Specific Isoforms of Pan-Neuronal Genes.

Profiling gene expression in single neurons using single-cell RNA-Seq is a powerful method for understanding the molecular diversity of the nervous system. Profiling alternative splicing in single neurons using these methods is more challenging, however, due to low capture efficiency and sensitivity. As a result, we know much less about splicing patterns and regulation across neurons than we do about gene expression. Here we leverage unique attributes of the C. elegans nervous system to investigate deep cell-specific transcriptomes complete with biological replicates generated by the CeNGEN consortium, enabling high-confidence assessment of splicing across neuron types even for lowly-expressed genes. Global splicing maps reveal several striking observations, including pan-neuronal genes that harbor cell-specific splice variants, abundant differential intron retention across neuron types, and a single neuron highly enriched for upstream alternative 3' splice sites. We develop an algorithm to identify unique cell-specific expression patterns and use it to discover both cell-specific isoforms and potential regulatory RNA binding proteins that establish these isoforms. Genetic interrogation of these RNA binding proteins in vivo identifies three distinct regulatory factors employed to establish unique splicing patterns in a single neuron. Finally, we develop a user-friendly platform for spatial transcriptomic visualization of these splicing patterns with single-neuron resolution.

Management of Desmoid Disease in Familial Adenomatous Polyposis.

Desmoid disease, though technically a benign condition, is nevertheless a leading cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP). Desmoid disease impacts approximately 30% of FAP patients, with several known risk factors. It runs the gamut in terms of severity-ranging from small, slow-growing asymptomatic lesions to large, focally destructive, life-threatening masses. Desmoids usually occur following surgery, and several patient risk factors have been established, including female sex, family history of desmoid disease, 3' APC mutation, and extraintestinal manifestations of FAP. Desmoid disease-directed therapy is individualized and impacted by desmoid stage, severity, postsurgical anatomy, and consequences of disease. Medical therapy consists of options in multiple classes of drugs: nonsteroidal anti-inflammatory drugs, hormonal therapy, tyrosine kinase inhibitors, and cytotoxic agents. Surgical excision is sometimes an option, but can be limited by common location of disease at the root of the small bowel mesentery. Palliative surgical treatments are often considered in management of desmoid disease. Intestinal transplantation for severe desmoid disease is an emerging and promising option, though long-term data on efficacy and survival is limited.

Transanal ileal pouch-anal anastomosis for inflammatory bowel disease: a systematic review and meta-analysis of short-term outcomes.

AIM: Restorative proctocolectomy with transabdominal ileal pouch-anal anastomosis (abd-IPAA) has become the standard surgical treatment for medically refractory ulcerative colitis (UC). However, it requires a technically difficult distal anorectal dissection and anastomosis due to the bony confines of the deep pelvis. To address these challenges, the transanal IPAA approach (ta-IPAA) was developed. This novel approach may offer increased visibility and range of motion compared with abd-IPAA, although its postoperative benefits remain unclear. The aim of this work was to perform a systematic review and meta-analysis to compare and inform the frequency of postoperative outcomes between ta-IPAA and abd-IPAA for patients with UC. METHOD: Several databases were searched from inception until May 2022 for studies reporting postoperative outcomes of patients undergoing ta-IPAA. Reviewers, working independently and in duplicate, evaluated studies for inclusion and graded the risk of bias. Odds ratios (OR), mean differences (MD) and prevalence ratio (PR) and their corresponding 95% confidence intervals (CIs) were calculated using random-effects models. Sensitivity analysis was performed. RESULTS: Ten retrospective studies comprising 284 patients with ta-IPAA were included. Total mesorectal excision was performed in 61.8% of cases and close rectal dissection in 27.9%. There was no difference in the odds of Clavien-Dindo (CD) I-II complications, CD III-IV and anastomotic leak (OR 0.96, 95% CI 0.27-3.40; OR 1.18, 95% CI 0.65-2.16; OR 1.37, 95% CI 0.58-3.23; respectively) between ta-IPAA and abd-IPAA. The ta-IPAA pooled CD I-II complication rate was 18% (95% CI 5%-35%) and for CD III-IV 10% (95% CI 5%-17%), and the anastomotic leak rate was 6% (95% CI 2%-10%). There were no deaths reported. CONCLUSIONS: This meta-analysis compared the novel ta-IPAA procedure with abd-IPAA and found no difference in postoperative outcomes. While the need for randomized controlled trails and comparison of functional outcomes between both approaches remains, this evidence should assist colorectal surgeons to decide if ta-IPAA is a viable alternative.

Outcome of incidental versus preoperatively diagnosed colorectal cancer during total proctocolectomy with ileal pouch-anal anastomosis for inflammatory bowel disease.

AIM: Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice for colorectal cancer (CRC) in inflammatory bowel disease. CRC may also be discovered incidentally at IPAA for other indications. We sought to determine whether incidentally found CRC at IPAA was associated with worse outcomes. METHODS: Our institutional pouch registry (1983-2021) was retrospectively reviewed. Patients with CRC at pathology after IPAA were divided into two groups: a preoperative diagnosis (PreD) group and an incidental diagnosis (InD) group. Their long-term outcomes (overall survival, disease-free survival and pouch survival) were compared. RESULTS: We included 164 patients: 53 (32%) InD and 111 (68%) PreD. There were no differences in cancer staging, differentiation and location. After a median follow-up of 11 (IQR 3-25) years for InD and 9 (IQR 3-20) years for the PreD group, deaths were 14 (26%) in the InD group and 18 (16%) in the PreD group. Pouch failures were five (9%) in the InD group and nine (8%) in the PreD group, of which two (5%) and four (4%) were cancer related. Ten-year overall survival was 94% for InD and 89% for PreD (P = 0.41), disease-free survival was 95% for InD and 90% for PreD (P = 0.685) and pouch survival was 89% for InD and 97% for PreD (P = 0.80). Pouch survival at 10 years was lower in rectal versus colon cancer (87% vs. 97%, P = 0.01). No difference was found in outcomes in handsewn versus stapled anastomoses. CONCLUSION: Inflammatory bowel disease patients with incidentally found CRC during IPAA appear to have similarly excellent oncological and pouch outcomes to patients with a preoperative cancer diagnosis.

Rediversion of the Failing Ileoanal Pouch: First Step in Pouch Salvage?

BACKGROUND: Ileal pouch-anal anastomosis is a technically demanding procedure with many potential complications. Rediversion with an ileostomy is often the first step in pouch salvage; however, it may not be clear if an individual patient will undergo subsequent pouch salvage surgery. We aimed to describe the indications and short- and long-term outcomes of rediversion in our pouch registry. METHODS: We queried our institutional pouch registry for patients who underwent index 2- or 3-stage IPAA and subsequent rediversion at our institution between 1985 and 2022. Pouches constructed elsewhere, rediverted elsewhere, or those patients who underwent pouch salvage/excision without prior rediversion were excluded. Patients were selected for pouch salvage according to the surgeon's discretion. RESULTS: Overall, 177 patients (3.4% of 5207 index pouches) were rediverted. At index pouch, median patient age was 32 years and 50.8% were women. Diagnoses included ulcerative colitis (86.4%), indeterminate colitis (6.2%), familial adenomatous polyposis (4.0%), and others (3.4%). Median time from prior ileostomy closure to rediversion was 7.2 years. Indications for rediversion were inflammatory in 98 (55.4%) and noninflammatory in 79 (44.6%) patients. After rediversion, 52% underwent pouch salvage, 30% had no further surgery, and 18.1% underwent pouch excision. The 5-year pouch survival rates for inflammatory and noninflammatory indications were 71.5% and 94.5%, respectively (P = .02). CONCLUSION: Rediversion of ileoanal pouches is a safe initial strategy to manage failing pouches and is a useful first step in pouch salvage in many patients. Subsequent salvage surgery for noninflammatory indications had a significantly higher pouch salvage rate than those rediverted for inflammatory complications.

Rediversion with an ileostomy was a safe, useful first step in pouch salvage, and subsequent salvage surgery for noninflammatory indications had a significantly higher pouch salvage rate than those rediverted for inflammatory complications.

Redo IPAA for long rectal cuff syndrome after ileoanal pouch for inflammatory bowel disease.

ABTRACT: BACKGROUND: When constructing an ileal pouch-anal anastomosis (IPAA), the rectal cuff should ideally be 1-2 cm long to avoid subsequent complications. METHODS: We identified patients from our IBD center who underwent redo IPAA for a long rectal cuff. Long rectal cuff syndrome (LRCS) was defined as a symptomatic rectal cuff ≥ 4 cm. RESULTS: Forty patients met the inclusion criteria: 42.5% female, median age at redo surgery 42.5 years. The presentation was ulcerative proctitis in 77.5% of the cases and outlet obstruction in 22.5%. The index pouch was laparoscopically performed in 18 patients (45%). The median rectal cuff length was 6 cm. The pouch was repaired in 16 (40%) cases, whereas 24 (60%) required the creation of a neo-pouch. At the final pathology, the rectal cuff showed chronic active colitis in 38 (90%) cases. After a median follow-up of 34.5 (IQR 12-109) months, pouch failure occurred in 9 (22.5%) cases. The pouch survival rate was 78% at 3 years. Data on the quality of life were available for 11 (27.5%) patients at a median of 75 months after redo surgery. The median QoL score (0-1) was 0.7 (0.4-0.9). CONCLUSION: LRCS, a potentially avoidable complication, presents uniformly with symptoms of ulcerative proctitis or stricture. Redo IPAA was restorative for the majority.

How to do a laparoscopic-assisted endoscopic 'clean sweep' for small bowel polyp clearance in Peutz Jeghers syndrome.

We demonstrate the technical details of laparoscopic-assisted endoscopic 'clean sweep' for small bowel polyp clearance in Peutz Jeghers Syndrome. A 'clean sweep' reduces the risk for future recurrences but was previously performed with an open technique. A minimally invasive approach is safe, reduces bowel trauma and has good postoperative outcomes.

The role of advanced endoscopy in appendiceal polyp management and outcomes.

BACKGROUND: Appendiceal orifice lesions are often managed operatively with limited or oncologic resections. The aim is to report the management of appendiceal orifice mucosal neoplasms using advanced endoscopic interventions. METHODS: Patients with appendiceal orifice mucosal neoplasms who underwent advanced endoscopic resections between 2011 and 2021 with either endoscopic mucosal resection (EMR), endoscopic mucosal dissection (ESD), hybrid ESD, or combined endoscopic laparoscopic surgery (CELS) were included from a prospectively collected dataset. Patient and lesion details and procedure outcomes are reported. RESULTS: Out of 1005 lesions resected with advanced endoscopic techniques, 41 patients (4%) underwent appendiceal orifice mucosal neoplasm resection, including 39% by hybrid ESD, 34% by ESD, 15% by EMR, and 12% by CELS. The median age was 65, and 54% were male. The median lesion size was 20 mm. The dissection was completed piecemeal in 49% of patients. Post-procedure, one patient had a complication within 30 days and was admitted with post-polypectomy abdominal pain treated with observation for 2 days with no intervention. Pathology revealed 49% sessile-serrated lesions, 24% tubular adenomas, and 15% tubulovillous adenomas. Patients were followed up for a median of 8 (0-48) months. One patient with a sessile-serrated lesion experienced a recurrence after EMR which was re-resected with EMR. CONCLUSION: Advanced endoscopic interventions for appendiceal orifice mucosal neoplasms can be performed with a low rate of complications and early recurrence. While conventionally lesions at the appendiceal orifice are often treated with surgical resection, advanced endoscopic interventions are an alternative approach with promising results which allow for cecal preservation.

Diagnosis and treatment of primary ileal pouch leaks: a 27-year experience at a referral center.

BACKGROUND: Ileal pouch-anal anastomosis (IPAA) is considered the preferred restorative surgical procedure for patients with ulcerative colitis and familial adenomatous polyposis requiring proctocolectomy. Unfortunately, postoperative leaks remain a complication with potentially significant ramifications. This study aimed to provide a comprehensive description of the evaluation, management, and outcomes of leaks after primary IPAA procedures. METHODS: Between 1995 and 2022, a total of 4058 primary IPAA procedures were performed at Cleveland Clinic. From a prospectively maintained pouch registry, we retrospectively reviewed the data of 237 patients who presented to the pouch center for management. Of these, 114 (3%) had undergone the index IPAA procedure at our clinic (de novo cases), whereas 123 patients had their index IPAA performed elsewhere. Data were missing for 43 patients, resulting in a final cohort of 194 patients. RESULTS: Our cohort had an average age of 41 years (range, 16-76) at the time of leak diagnosis. Overall, 55.2% were males, average body mass index was 24.4 kg/m2, and pain was the most prevalent presenting symptom (61.8%), followed by fever (34%). Leaks were confirmed through diagnostic testing in 141 cases, whereas 27.3% were detected intraoperatively. The most common initial diagnoses were pelvic abscess (47.4%) and enteric fistulas (26.8%), including cutaneous (9.8%), vaginal (7.2%), and bladder fistulas (3.1%). By location, leaks occurred at the tip of the "J" (52.6%), at the pouch-anal anastomotic site (35%), and in the body of the pouch (12.4%). A nonoperative management approach was initially attempted in 49.5% of cases, including antibiotic therapy, drainage, endoclip, and endo-sponge, with a success rate of 18.5%. Surgery was eventually required in 81.4% of patients, including (1) sutured or stapled pouch repair (52.5%), with diversion performed in 87.9% of these cases either before or during the salvage surgery; (2) pouch excision with neo-IPAA (22.7%), including 9 patients from the first group; and (3) pouch disconnection, repair, and reanastomosis (9.3%). Pouch failure occurred in 8.4%, with either pouch excision (11.1%) or permanent diversion (4.5%). Ultimately, 12.4% of patients (24 of 194) required permanent diversion, with all necessitating pouch excision. In the 30-day follow-up after salvage surgery, short-term complications arose in 38.7% of patients. The most common complications observed were ileus, pelvic abscess/sepsis, and fever. CONCLUSION: Leaks after primary IPAA procedures represent an infrequent, yet challenging, complication. Despite attempts at nonoperative management, the success rate is limited. Salvage surgery is associated with a high pouch retention rate, underscoring its importance in the management of post-IPAA leaks.

Perioperative outcomes of ileorectal anastomosis - an analysis of 823 patients.

AIM: Ileorectal anastomosis (IRA) following total abdominal colectomy (TAC) allows for resortation of bowel continuity but prior studies have reported rates of anastomotic leak (AL) to be as high as 23%. We aimed to report rates of AL and complications in a large cohort of patients undergoing IRA. We hypothesized that AL rates were lower than previously reported and that selective use of diverting loop ileostomy (DLI) is associated with decreased AL rates. METHOD: Patients undergoing TAC or end-ileostomy reversal with IRA, with or without DLI, between 1980 and 2021 were identified from a prospectively maintained institutional database and retrospectively analysed. Redo IRA cases were excluded. Short-term (30-day) surgical outcomes were collected using our database. AL was defined using a combination of imaging and, in the case of return to the operating room, intraoperative findings. RESULTS: Of 823 patients in the study cohort, DLI was performed in 27% and performed more frequently for constipation and inflammatory bowel disease. The overall AL rate was 3% (1% and 4% in those with and without DLI, respectively) and diversion was found to be protective against leak (OR 0.28, 95% CI 0.08-0.94, p = 0.04). However, patients undergoing diversion had a higher overall rate of postoperative complications (51% vs. 36%, p < 0.001) including superficial wound infection, urinary tract infection, dehydration, blood transfusion and portomesenteric venous thrombosis (all p < 0.04). CONCLUSION: Our study represents the largest series of patients undergoing IRA reported to date and demonstrates an AL rate of 3%. While IRA appears to be a viable surgical option for diverse indications, our study underscores the importance of careful patient selection and thoughtful consideration of staging the anastomosis and temporary faecal diversion when necessary.

Plasma metabolomic differences in early-onset compared to average-onset colorectal cancer.

Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or  ≥ 60 years (aoCRC or older non-CRC controls). Differential metabolite abundance and metabolic pathway analyses were performed on plasma samples. Multivariate Cox proportional hazards modeling was used for survival analyses. All P values were adjusted for multiple testing (false discovery rate, FDR P < 0.15 considered significant). The study population comprised 170 patients with CRC (66 eoCRC and 104 aoCRC) and 49 non-CRC controls (34 young and 15 older). Citrate was differentially abundant in aoCRC vs. eoCRC in adjusted analysis (Odds Ratio = 21.8, FDR P = 0.04). Metabolic pathways altered in patients with aoCRC versus eoCRC included arginine biosynthesis, FDR P = 0.02; glyoxylate and dicarboxylate metabolism, FDR P = 0.005; citrate cycle, FDR P = 0.04; alanine, aspartate, and glutamate metabolism, FDR P = 0.01; glycine, serine, and threonine metabolism, FDR P = 0.14; and amino-acid t-RNA biosynthesis, FDR P = 0.01. 4-hydroxyhippuric acid was significantly associated with overall survival in all patients with CRC (Hazards ratio, HR = 0.4, 95% CI 0.3-0.7, FDR P = 0.05). We identified several unique metabolic alterations, particularly the significant differential abundance of citrate in aoCRC versus eoCRC. Arginine biosynthesis was the most enriched by the differentially altered metabolites. The findings hold promise in developing strategies for early detection and novel therapies.

Distinct intratumoral microbiome of young-onset and average-onset colorectal cancer.

BACKGROUND: The unexplained rise of young-onset CRC (yoCRC, age <50 years) is of concern. Evidence suggests that microbial dysbiosis may be a contributing factor, but the tumor microbial profile of yoCRC in comparison to average-onset CRC (aoCRC, age >60) has not been fully investigated. METHODS: 16S rRNA amplicon sequencing was performed in tumor and paired adjacent non-malignant fresh frozen tissue specimens prospectively collected from 136 yoCRC and 140 aoCRC patients. Phyloseq, microbiomeSeq, metagenomeSeq, and NetComi were utilized for bioinformatics analysis. Statistical tests included Fisher's exact test, ANOVA, PERMANOVA with Bonferroni correction, linear regression, and Wilcoxon test. p-value <0.05 was considered statistically significant. FINDINGS: yoCRC patients were more likely to have left-sided (72.8 vs. 54.3%), rectal (36.7% vs. 25%), and stage IV (28% vs. 15%) tumors. yoCRC tumors had significantly higher microbial alpha diversity (p = 1.5 × 10-5) and varied beta diversity (R2 = 0.31, p = 0.013) than aoCRC tumors. yoCRC tumors were enriched with Akkermansia and Bacteroides, whereas aoCRC tumors showed greater relative abundances of Bacillus, Staphylococcus, Listeria, Enterococcus, Pseudomonas, Fusobacterium, and Escherichia/Shigella. Akkermansia had a predominantly negative correlation with the microbial communities in yoCRC tumors. yoCRC and aoCRC tumors had distinct microbial profiles associated with tumor location, sidedness, stage, and obesity. Fusobacterium (R2 = -0.23, p = 0.001) and Akkermansia (R2 = 0.05, p = 0.001) abundance correlated with overall survival in yoCRC. INTERPRETATION: Our study provides a comprehensive understanding of the microbial perturbations in yoCRC tumors. We identify microbial candidates that may highlight a distinct pathogenesis of yoCRC and serve as preventive, diagnostic, and therapeutic targets. FUNDING: Sondra and Stephen Hardis Chair in Oncology Research (A.A.K.).