Surgical management of colon cancer in ulcerative colitis patients with orthotopic liver transplant for primary sclerosing cholangitis. A systematic review.

INTRODUCTION: Colon cancer in ulcerative colitis patients with liver transplant (UCCOLT) due to primary sclerosing cholangitis carries significant treatment challenges. Aim of this literature search is to review management strategies and provide a framework to facilitate the decisional process in this clinical setting. METHODS: PRISMA-compliant systematic search was followed by critical expert commentary of the results and development of a surgical management algorithm. Endpoints included surgical management, operative strategies, functional and survival outcomes. Technical and strategics aspects with particular regard to the choice of reconstruction were evaluated to tentatively develop an integrated algorithm. RESULTS: Ten studies reporting treatment of 20 UCCOLT patients were identified after screening. Nine patients underwent proctocolectomy and end-ileostomy (PC) and eleven had restorative ileal pouch-anal anastomosis (IPAA). Reported results for perioperative outcomes, oncological outcomes, and graft loss were comparable for both procedures. There were no reports of subtotal colectomies and ileo-rectal anastomosis (IRA). CONCLUSIONS: Literature in the field is scarce and decision-making is particularly complex. PC and IPAA have been reported with good results. Nevertheless, IRA may also be considered in UCCOLT patients in selected cases, reducing the risks of sepsis, OLT and pouch failure; furthermore, in young patients, it has the advantage of preserving fertility or sexual function. The proposed treatment algorithm may represent a valuable support in guiding surgical strategy.

Influence of COVID-19 Pandemic on Colorectal Cancer Presentation, Management and Outcome during the COVID-19 Pandemic.

The aim of the study was to investigate whether the COVID-19 pandemic and related measures had an influence on colorectal cancer (CRC) presentation, management, and outcomes; it was a retrospective monocentric study. CRC patients undergoing surgery during the COVID-19 pandemic (1 March 2020-28 February 2022) (group B) were compared with patients operated on in the previous two years (1 March 2018-29 February 2020) in the same unit (group A). The primary outcome was to investigate whether there were differences in concern regarding the stage at presentation, as a whole and after dividing groups based on cancer location (right colon cancer, left colon cancer, rectal cancer). Secondary outcomes included differences in the number of patients admitted from emergency departments and emergency surgeries between periods, and differences in the postoperative outcomes. A subanalysis within the pandemic group was conducted on the same outcomes, dividing the aforementioned group based on pandemic trends. Two hundred and eighty (280) were operated on during the study period: 147 in group A and 133 in group B. Stage at presentation was similar between groups; however, the subgroups analysis showed that in the pandemic group, the number of early-stage left colon cancer occurrences almost halves, yet not significantly. Emergency department referral was more common in group B (p-value: 0.003); in group B, they also had longer operations and there was a more frequent use of ostomy. No differences in the number of postoperative complications nor in the postoperative outcomes were found. Patients with CRC were more frequently referred through the emergency department during the COVID-19 pandemic and left-sided cancers appear to be generally diagnosed at a more advanced stage. Postoperative outcomes showed that high specialized colorectal units can deliver standard high-level treatment under high-pressure external conditions.

Metachronous peritoneal metastases in patients with pT4b colon cancer: An international multicenter analysis of intraperitoneal versus retroperitoneal tumor invasion.

BACKGROUND: It was hypothesized that colon cancer with only retroperitoneal invasion is associated with a low risk of peritoneal dissemination. This study aimed to compare the risk of metachronous peritoneal metastases (mPM) between intraperitoneal and retroperitoneal invasion. METHODS: In this international, multicenter cohort study, patients with pT4bN0-2M0 colon cancer who underwent curative surgery were categorized as having intraperitoneal invasion (e.g. bladder, small bowel, stomach, omentum, liver, abdominal wall) or retroperitoneal invasion only (e.g. ureter, pancreas, psoas muscle, Gerota's fascia). Primary outcome was 5-year mPM cumulative rate, assessed by Kaplan-Meier analysis. RESULTS: Out of 907 patients with pT4N0-2M0 colon cancer, 198 had a documented pT4b category, comprising 170 patients with intraperitoneal invasion only, 12 with combined intra- and retroperitoneal invasion, and 16 patients with retroperitoneal invasion only. At baseline, only R1 resection rate significantly differed: 4/16 for retroperitoneal invasion only versus 8/172 for intra- +/- retroperitoneal invasion (p = 0.010). Overall, 22 patients developed mPM during a median follow-up of 45 months. Two patients with only retroperitoneal invasion developed mPM, both following R1 resection. The overall 5-year mPM cumulative rate was 13% for any intraperitoneal invasion and 14% for retroperitoneal invasion only (Log Rank, p = 0.878), which was 13% and 0%, respectively, in patients who had an R0 resection (Log Rank, p = 0.235). CONCLUSION: This study suggests that pT4b colon cancer patients with only retroperitoneal invasion who undergo an R0 resection have a negligible risk of mPM, but this is difficult to prove because of its rarity. This observation might have implications regarding individualized follow-up.

Mesenteric closure with polymer-ligating clips after right colectomy with complete mesocolic excision for cancer and mesentery-based ileocolic resection for Crohn's disease.

Mesenteric closure following right colectomy remains controversial and, following the advent of laparoscopic surgery, many surgeons do not routinely close the mesentery after colorectal resection. Nevertheless, especially after the introduction of operations such as right colectomy with complete mesocolic excision and ileocolic resections with extensive mesentery removal for Crohn's disease, the wide mesenteric defect resulting from the dissections can certainly expose the patients to complications such as internal hernias or volvuli. In general, mesenteric closure requires intracorporeal suturing. We describe a simple technique for the closure of the mesentery after surgical resection using polymer-ligating clips. This novel technique seems to minimize the time, effort and risk inherent to the procedure, even after large mesenteric excisions.

Volume-outcome relationship in rectal cancer surgery.

INTRODUCTION: Hospital centralization effect is reported to lower complications and mortality for high risk and complex surgery operations, including colorectal surgery. However, no linear relation between volume and outcome has been demonstrated. Aim of the study was to evaluate the increased surgical volume effect on early outcomes of patient undergoing laparoscopic restorative anterior rectal resection (ARR). METHODS: A retrospective analysis of all consecutive patients undergoing ARR with primary anastomosis between November 2016 and December 2020 after centralization of rectal cancer cases in an academic Centre. Short-term outcomes are compared to those of patients operated in the same unit during the previous 10 years before service centralization. The primary outcome was estimated anastomotic leak rate. Mean operative time, need of conversion, postoperative use of blood transfusion, radicality, in-hospital stay, number and type of complications, readmission and reoperation rate, mortality and 1-year and stoma persistence rates were evaluated as secondary outcomes. RESULTS: 86 patients were operated in the study period and outcomes compared to those of 101 patients operated during the previous ten years. Difference in volume of surgery was significant between the two periods (p 0.019) and the estimated leak rate was significantly lower in the higher volume unit (p 0.047). Mean operative time, need of conversion, postoperative use of blood transfusion and in-hospital stay (p < 0.05) were also significantly reduced in Group A. CONCLUSION: This study suggests that the shift toward higher volume in rectal cancer surgery is associated to decreased anastomotic leak rate. Potentiation of lower volume surgical units may yield optimal perioperative outcomes.

Pathophysiology of Crohn's disease inflammation and recurrence.

Chron's Disease is a chronic inflammatory intestinal disease, first described at the beginning of the last century. The disease is characterized by the alternation of periods of flares and remissions influenced by a complex pathogenesis in which inflammation plays a key role. Crohn's disease evolution is mediated by a complex alteration of the inflammatory response which is characterized by alterations of the innate immunity of the intestinal mucosa barrier together with a remodeling of the extracellular matrix through the expression of metalloproteins and increased adhesion molecules expression, such as MAcCAM-1. This reshaped microenvironment enhances leucocytes migration in the sites of inflammation, promoting a TH1 response, through the production of cytokines such as IL-12 and TNF-α. IL-12 itself and IL-23 have been targeted for the medical treatment of CD. Giving the limited success of medical therapies, the treatment of the disease is invariably surgical. This review will highlight the role of inflammation in CD and describe the surgical approaches for the prevention of the almost inevitable recurrence.

The Role of Active Inflammation and Surgical Therapy in Crohn's Disease Recurrence.

An altered balance between effector and regulatory factors is supposed to sustain the tissue-damaging immune response in inflammatory bowel disease (IBD). Several studies demonstrate that severe active inflammation is a strong predictor for surgical complications and recurrence. Indeed, bowel resection in Crohn's disease (CD) patients has a high surgical recurrence rate. In this review, we examined the IBD inflammatory pathways, the current surgical treatments, and the almost inevitable recurrence. The question that might arise is if the cure of intestinal CD is to be found in the surgical approach. A selective search of two databases (PubMed and the Cochrane Library) has been carried out without considering a specific time horizon as inclusion criteria. The scope of this literature review was investigating on the role of inflammation in the management of CD. The following key words have been used to develop the query string: (i) inflammation; (ii) Crohn's disease; (iii) surgery; and (iv) postsurgical recurrence.

Histotype influences emergency presentation and prognosis in colon cancer surgery.

AIM: To investigate whether differences in histotype in colon cancer correlate with clinical presentation and if they might influence oncological outcomes and survival. METHODS: Data regarding colon cancer patients operated both electively or in emergency between 2009 and 2014 were retrospectively collected from a prospectively maintained database and analyzed for the purpose of this study. Rectal cancer was excluded from this analysis. Statistical univariate and multivariate analyses were performed to investigate possible significant variables influencing clinical presentation, as well as oncological outcomes and survival. RESULTS: Data from 219 patients undergoing colorectal resection for cancer of the colon only were retrieved. One hundred seventy-four patients had an elective procedure and forty-five had an emergency colectomy. Emergency presentation was more likely to occur in mucinous (p < 0.05) and signet ring cell (p < 0.01) tumors. No definitive differences in 5-year overall (44.7% vs. 60.6%, p = 0.078) and disease-free (51.2% vs. 64.4%, p = 0.09) survival were found between the two groups as a whole, but the T3 emergency patients showed worse prognosis than the elective (p < 0.03). Lymph node invasion, laparoscopy, histology, and blood transfusions were independent variables found to influence survival. Distribution assessed for pTNM stage showed T3 cancers were more common in emergency (p < 0.01). CONCLUSIONS AND DISCUSSION: Mucinous and signet ring cell tumors are related to emergency presentation, pT3 stage, poorest outcomes, and survival. Disease-free survival in patients who had emergency surgery for T3 colon cancer seems related to the histotype.

C-reactive protein levels in the perioperative period as a predictive marker of endoscopic recurrence after ileo-colonic resection for Crohn's disease.

The aim of this study was to determine the perioperative behavior of C-reactive protein (CRP) in Crohn's disease (CD) patients undergoing elective ileo-cecal (IC) resection and to identify association between perioperative CRP levels and endoscopic recurrence at 1 year. Study hypothesis was that perioperative CRP changes are disease specific and could detect subset of patients with more aggressive pathopysiology. Seventy-five patients undergoing IC resection for CD were prospectively enrolled. Serial CRP levels were assessed: preoperative, postoperative day 1 (POD1) and day 5 (POD5). CD patients' values were compared against same interval assessments of control groups undergoing right colectomy and appendicectomy. At POD1, the serum concentration increase was significantly higher in CD patients than in controls. Comparing with control groups, CRP levels remained remarkably high and showed a lower reduction in CD at POD5. Difference between groups was statistically significant. Optimal cutoff levels have been identified: serum CRP concentrations of >39.8 mg/l at POD1 and of >23.2 mg/l at POD5 have shown a significant association to endoscopic recurrence when using bivariate correlation. In this preliminary series, binary logistic regression could not demonstrate statistical relationship between endoscopic recurrence and any of the variables evaluated as prognostic factor. This is the only study so far that investigates and confirms a disease-specific upregulation of CRP response in the perioperative period for CD patients undergoing surgery. The postoperative CRP levels and kinetics seem to be related to the grade of mucosal inflammation and recurrence rate according to our 12 months endoscopic evaluation.

Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.

Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of STAT3/NF-kB-activating cytokines in the neoplastic areas. These data suggest that strategies aimed at the cotargeting of STAT3/NF-kB activation and interaction between them might represent an attractive and novel approach to combat CRC.

Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut.

In inflammatory bowel disease (IBD), tissue damage is driven by an excessive immune response, poorly controlled by counter-regulatory mechanisms. SIRT1, a class III NAD+-dependent deacetylase, regulates negatively the expression of various proteins involved in the control of immune-inflammatory pathways, such as Stat3, Smad7, and NF-κB. Here we examined the expression, regulation, and function of SIRT1 in IBD. SIRT1 RNA and protein expression was less pronounced in whole biopsies and lamina propria mononuclear cells (LPMCs) of IBD patients in comparison with normal controls. SIRT1 expression was downregulated in control LPMC by tumor necrosis factor (TNF)-α and interleukin (IL)-21, and upregulated in IBD LPMC by neutralizing TNF-α and IL-21antibodies. Consistently, SIRT1 expression was increased in mucosal samples taken from IBD patients successfully treated with Infliximab. Treatment of IBD LPMC with Cay10591, a specific SIRT1 activator, reduced NF-κB activation and inhibited inflammatory cytokine synthesis, whereas Ex527, an inhibitor of SIRT1, increased interferon (IFN)-γ in control LPMC. SIRT1 was also reduced in mice with colitis induced by 2,4,6-trinitrobenzenesulphonic acid or oxazolone. Cay10591 prevented and cured experimental colitis whereas Ex527 exacerbated disease by modulating T cell-derived cytokine response. Data indicate that SIRT1 is downregulated in IBD patients and colitic mice and suggest that SIRT1 activation can help attenuate inflammatory signals in the gut.

A functional role for Smad7 in sustaining colon cancer cell growth and survival.

Initially identified as an inhibitor of transforming growth factor (TGF)-ß mainly owing to its ability to bind TGF-ß receptor type I and abrogate TGF-ß-driven signaling, Smad7 can interact with additional intracellular proteins and regulate TGF-ß-independent pathways, thus having a key role in the control of neoplastic processes in various organs. Genome-wide association studies have shown that common alleles of Smad7 influence the risk of colorectal cancer (CRC), even though the contribution of Smad7 in colon carcinogenesis is not fully understood. In this study, we assessed the expression and role of Smad7 in human and mouse models of sporadic CRC. We document a significant increase of Smad7 in human CRC relative to the surrounding nontumor tissues and show that silencing of Smad7 inhibits the growth of CRC cell lines both in vitro and in vivo after transplantation into immunodeficient mice. Knockdown of Smad7 results in enhanced phosphorylation of the cyclin-dependent kinase (CDK)2, accumulation of CRC cells in S phase and enhanced cell death. Smad7-deficient CRC cells have lower levels of CDC25A, a phosphatase that dephosphorylates CDK2, and hyperphosphorylated eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, knockdown of Smad7 associates with inactivation of eIF2α, lower CDC25A expression and diminished fraction of proliferating cells in human CRC explants, and reduces the number of intestinal tumors in Apc(min/+) mice. Altogether, these data support a role for Smad7 in sustaining colon tumorigenesis.

Endoscopic vs ultrasonographic findings related to Crohn's disease recurrence: a prospective longitudinal study at 3 years.

BACKGROUND AND AIMS: Ileocolonoscopy (IC) is the gold standard for assessing Crohn's Disease (CD) recurrence after ileo-colonic resection. In a prospective longitudinal study we compared findings related to CD recurrence when using techniques visualizing either the luminal or the extraluminal surface (IC and small bowel follow through, SBFT vs Small Intestine Contrast Ultrasonography, SICUS). METHODS: From 2003 to 2008, 25 CD patients undergoing ileo-colonic resection were enrolled. Clinical assessment (CDAI) was performed at 1, 2 and 3 years. IC was performed at 1 (n=25) and 3 years (n=15), SBFT at 2 years (n=21) and SICUS at 1 (n=25), 2 (n=21) and 3 years (n=15). Recurrence was assessed by SBFT and SICUS (bowel wall thickness, BWT) when using IC as gold standard. RESULTS: At 1 year, all patients were inactive and recurrence was detected by IC in 24/25 (96%) and by SICUS in 25/25 patients. At 2 years, 6/21 patients (29%) were active and recurrence was detected by SBFT in 12/21 (57%) and by SICUS in 21/21 patients. At 3 years, 5/15 patients (33%) were active, IC showed recurrence in 14/15 (93%), and SICUS in 15/15 patients. The endoscopic score at 1 year was higher in patients developing relapse at 2 years (n=5) than in patients maintaining remission (n=10) (median: 4, range 3-4 vs 2, range 0-3; p=0.003). The same finding was not observed by using SICUS (median BWT at 1 year: 5, range 4-7 vs 3.7, range 3.5-6; p=0.19). CONCLUSIONS: Although IC and SICUS provide a different view of the bowel wall, in experienced hands SICUS provides findings compatible with endoscopic recurrence after ileo-colonic resection for CD. Discrepant findings may be observed in a low proportion of patients with minor lesions related to CD recurrence.

Non-invasive techniques for assessing postoperative recurrence in Crohn's disease.

Postoperative recurrence after ileo-colonic resection is a feature of Crohn's Disease (CD), almost 73% of patients show endoscopic recurrence at 1 year and 90% at 3 years. After surgical resection for CD, symptoms may be related to the surgical resection itself. Moreover, the development of an early severe endoscopic recurrence within 1 year represents a risk factor for early clinical recurrence. On the basis of these observations, the early detection and assessment of asymptomatic endoscopic recurrence may allow a timely and appropriate treatment of CD patients after ileo-colonic resection. At this purpose, conventional colonoscopy with ileoscopy currently represents the gold standard for assessing CD recurrence, graded according to the Rutgeerts' score. Lesions compatible with CD recurrence can be also detected by conventional radiology, including small bowel follow through and enema, both associated with a high radiation exposure. Due to the ineluctable course of CD after resection, and to the need of a proper follow up for assessing CD recurrence, several alternative, non invasive techniques have been searched in order to assess the post-operative recurrence, including: faecal alpha 1-antitrypsin clearance, faecal calprotectin, 99Tc-HMPAO scintigraphy, virtual colonoscopy, ultrasonography and, more recently, wireless capsule endoscopy (WCE) and Small Intestine Contrast Ultrasonography (SICUS). Among these, current evidences suggest that in experienced hands, ultrasound examination by SICUS represents a non-invasive technique useful for assessing recurrence in CD patients under regular follow up after surgery. The same findings are suggested for WCE, although the impact risk related to the recurrence or to the surgical anastomosis itself limits the use of this non-invasive technique for assessing CD recurrence after surgery.