Patient colon and rectal operative outcomes when treated with immune checkpoint inhibitors.

There is limited data about the safety of colorectal surgery after immune checkpoint inhibitors (ICI). We aimed to share our experience about postoperative outcomes of colorectal surgery for patients treated with ICI. Overall, 31 patients were identified, 22 (71%) underwent elective and nine (29%) underwent emergent/urgent surgery. The 30-day Clavien Dindo class ≥ III complication rates were 27.3% (n = 6) for elective and 55.5% (n = 5) for emergent/urgent cases. Four patients underwent emergency surgery for immune-related colonic perforation and developed postoperative septic shock; two died. Considering patients' comorbidities, cancer stage, and surgical complexity, elective colorectal surgery after ICI seems relatively safe. However, emergent/urgent colorectal surgery was associated with high postoperative morbidity. Indeed, colonic perforation in the setting of ICI treatment has a significant risk of postoperative mortality. Therefore, for patients on ICI with any acute abdominal symptoms, surgical consult should be involved, and colon perforation should be ruled out.

Toll-like receptor 4 regulates intestinal fibrosis via cytokine expression and epithelial-mesenchymal transition.

Intestinal fibrosis induced by chronic and recurrent colitis, which is exacerbated by bowel stenosis, stricture, and obstruction, is challenging to treat. Toll-like receptor 4 (TLR4) stimulates innate and acquired immunity in response to specific microbial components, but the role of TLR4 in intestinal fibrosis is largely unknown. We investigated its role in intestinal fibrosis using not only a murine fibrosis model but also human myofibroblasts and intestinal epithelial cells. Colon fibrosis was induced in TLR4-deficient (TLR4-/-) mice and its wild-type counterparts with 3% dextran sulfate sodium. Absence of TLR4 gene attenuated chronic inflammation and colonic macrophages infiltration; intestinal fibrosis and collagen deposition were suppressed. Also, the production of tumor necrosis factor-α, interleukin-12p40, and transforming growth factor-ß was reduced in TLR4-deficient peritoneal macrophages. TLR4 was silenced in CCD-18Co cells by small interfering RNA (siRNA), and matrix metalloproteinase-1, tissue inhibitor of metalloproteinase, and collagen α1 expression was evaluated. Role of TLR4 in epithelial-mesenchymal transition (EMT) was evaluated in HCT116 cells. Suppression of TLR4 transcription by siRNAs affected myofibroblasts activity, collagen synthesis, and EMT in the human cancer cell line. Thus, we suggest that TLR4 can be an essential mediator in intestinal chronic inflammation and fibrosis, indicating that TLR4 signaling is a potential therapeutic target for intestinal fibrosis.

Role of Inflammation in Pathophysiology of Colonic Disease: An Update.

Diseases of the colon are a big health burden in both men and women worldwide ranging from acute infection to cancer. Environmental and genetic factors influence disease onset and outcome in multiple colonic pathologies. The importance of inflammation in the onset, progression and outcome of multiple colonic pathologies is gaining more traction as the evidence from recent research is considered. In this review, we provide an update on the literature to understand how genetics, diet, and the gut microbiota influence the crosstalk between immune and non­immune cells resulting in inflammation observed in multiple colonic pathologies. Specifically, we focus on four colonic diseases two of which have a more established association with inflammation (inflammatory bowel disease and colorectal cancer) while the other two have a less understood relationship with inflammation (diverticular disease and irritable bowel syndrome).

Primary classic Hodgkin lymphoma of the ileum and Epstein-Barr virus mucocutaneous ulcer of the colon: two entities compared.

Primary classic Hodgkin lymphoma of the gastrointestinal tract represents a rare occurrence. A full patient's work-up is essential in order to exclude a secondary intestinal involvement. Histologically Epstein-Barr virus mucocutaneous ulcer closely resembles Hodgkin lymphoma. The differential diagnosis between these two entities is relevant, since both the therapeutic approach and the clinical behavior are different. Herein, we describe a case of primary classic Hodgkin lymphoma arising in the ileum and a case of Epstein-Barr virus mucocutaneous ulcer of the colon, focusing on the main clinicopathological differences.

Recipient mucosal-associated invariant T cells control GVHD within the colon.

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I-like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A-/- and MR1-/- mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT.

Protective properties of combined fungal polysaccharides from Cordyceps sinensis and Ganoderma atrum on colon immune dysfunction.

In vivo an ecological network of polysaccharides utilization by gut microbiota is not only an intense competition but also an impressive cooperation pattern. The present study evaluated the in vivo protective effect of combined fungal polysaccharides (CFP) from Cordyceps sinensis and Ganoderma atrum on colon immune dysfunction, induced by 150mg/kg cyclophosphamide (CP). The results showed that C. sinensis polysaccharides (CSP) significantly promoted microbial-derived butyrate to improve histone h3 acetylation mediating regulatory T (Treg) cell specific Foxp3, as well as significantly restored CP-induced elevation of interleukin (IL)-17 and IL-21. Additionally, G. atrum polysaccharides (PSG) significantly down-regulated MyD88, as well as significantly increased IL-10 and TGF-ß3. Furthermore, CFP balanced the disequilibrium of cytokines secretion and Foxp3/RORγt ratio related Treg/T helper 17 (Th17) balance, as well as down-regulated the TLR-mediated inflammatory signaling pathway and promoted secretory immunoglobulin A (sIgA) secretion to suppress colonic inflammation. Therefore, our results typically contribute to understand the in vivo immunoregulatory function of fungal polysaccharides compounds, involving microbial-associated inflammatory signals and specific metabolic products.

Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis.

AIM: To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy. METHODS: We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used. RESULTS: A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported. CONCLUSION: In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.

A bleeding colonic ulcer from invasive Aspergillus infection in an immunocompromised patient: a case report.

INTRODUCTION: Invasive Aspergillus commonly involves the lungs, but can also affect other organs such as the skin, adrenal glands, central nervous system, liver, spleen and the gastrointestinal tract. Gastrointestinal aspergillosis is rare and is most often discovered in immunocompromised patients. There is only one other case report to our knowledge that describes the diagnosis being discovered on histopathological analysis of endoscopic biopsies of necrotic ulcers. CASE PRESENTATION: A 36-year-old Hispanic woman presented with septic shock secondary to extensive Fournier gangrene that required multiple surgical debridement of the perineal and retroperitoneal area. Her vital signs on admission were a temperature of 39.4°C and blood pressure of 85/56 mmHg, pulse rate of 108/min and respiratory rate of 25. An examination of the perineum/genital area revealed bilateral gluteal and perilabial edema, erythema and focal areas of necrotic tissue with purulent discharge. Other surgeries included small bowel resections with ileoileal anastomosis that later developed an anastomotic leak that required and diverting end ileostomy. Eleven weeks after admission, our patient developed hematochezia from the colostomy associated with a decrease in hemoglobin and hematocrit to 6.4 g/dL and 20.2% respectively. Colonoscopy through the ostomy revealed blood throughout the colon and a 3 cm necrotic ulcer with an adherent clot in the transverse colon. Biopsies were taken from the edge of the ulcer. Histopathological analysis of the specimen with Grocott's methenamine silver stain revealed septated hyphae with the 45-degree-angle branching that is morphologically consistent with Aspergillus species. Our patient was treated with intravenous voriconazole for 30 days with a prolonged hospitalization but no recurrent bleeding. CONCLUSIONS: Gastrointestinal aspergillosis is an unusual presentation of invasive Aspergillus associated with a high mortality rate. Characteristic features of gastrointestinal aspergillosis include invasion of the mesenteric arteries, intravascular thrombosis and subsequent tissue ischemia. Clinical manifestations of invasive Aspergillus of the gastrointestinal tract can include fever, abdominal pain, ileus, peritonitis, bloody diarrhea or hematochezia. In an autopsy series of patients with invasive Aspergillus, 37 of 107 patients had Aspergillus involvement of the gastrointestinal system; the most common pathological findings included ulcers and abscesses. Although rare, invasive aspergillosis may present with gastrointestinal bleeding associated with necrotic ulcers on endoscopic examination.

Cytokine gene expression in intestinal tuberculosis and Crohn's disease.

BACKGROUND: Intestinal tuberculosis (TB) and Crohn's disease closely resemble each other clinically and morphologically. Little is known of cytokine regulation in intestinal TB. OBJECTIVE: To compare cytokine gene expression in colonic mucosa and peripheral blood mononuclear cells (PBMC) in TB with that in Crohn's disease. METHODS: Biopsies were obtained from normal and ulcerated colonic mucosa of 12 intestinal TB and 11 Crohn's disease patients, and PBMC from 15 intestinal TB and 12 Crohn's disease patients and 11 healthy volunteers. RNA was extracted, and the expression of selected cytokines, chemokines and pattern recognition receptors quantified by reverse transcriptase real-time polymerase chain reaction using SYBR green. RESULTS: The mRNA expression of interleukin-8 (IL-8), induced protein-10, tumour necrosis factor-alpha, IL-23 p19 and IL-12 p40, and Toll-like receptors (TLR) 1 and 2 in the ulcerated mucosa was increased in both intestinal TB and Crohn's disease. Expression of growth-related oncogene-alpha was increased in intestinal TB, while expression of interferon-gamma (IFN-) and TLR 4, 5 and 9 was increased in Crohn's disease. Expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) was decreased in Crohn's disease. Secretion of IFN- or IL-10 from PBMC was not significantly altered in either disease. PBMC mRNA expression of IL-1, IL-6 and IL-8 mRNA was upregulated in Crohn's disease, while that of IL-17 was upregulated in intestinal TB. CONCLUSIONS: Cytokine gene expression patterns in intestinal mucosa and PBMC of intestinal TB were remarkably similar to Crohn's disease, and demonstrated innate immune activation and T-helper 1 polarisation.

Colonic involvement in disseminated histoplasmosis of an immunocompetent adult: case report and literature review.

BACKGROUND: Histoplasmosis is a common opportunistic fungal infection that is observed almost exclusively in immunodeficient patients, especially those with AIDS. Immunocompetent individuals that suffer from histoplasmosis are rarely reported, especially those with disseminated lesions, such as disseminated histoplasmosis. The observation of disseminated histoplasmosis with prominent gastrointestinal involvement, no respiratory symptoms (which is presumed to be the portal of infection), gastrointestinal pathological changes, and minor digestive system disorders make this case study exceedingly rare. CASE PRESENTATION: We report the case of a 33-year-old immunocompetent male who presented with fever and weight loss. Based on investigations, the patient showed pancytopenia, hepatosplenomegaly, bone marrow involvement and marked colonic involvement. Finally, disseminated histoplasmosis was diagnosed and confirmed by stained smears of fine needle aspirates and biopsy from lesions in the bone marrow and colon. The patient showed appreciable regression of lesions following prompt treatment with amphotericin B deoxycholate, and was treated thereafter with oral itraconazole following discharge from hospital. CONCLUSION: Disseminated histoplasmosis could be underestimated in immunocompetent patients. A high degree of clinical suspicion is essential in both immunocompromised and immunocompetent patients, regardless of pulmonary symptoms, and whether in endemic or non-endemic areas. Early and accurate diagnosis is extremely important for the appropriate treatment of infection and to improve disease outcome.

Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn's disease.

BACKGROUND: Glycoprotein 2 (GP2) was discovered as the major autoantigen of Crohn's disease (CD)-specific pancreatic autoantibodies (PAB). We investigated anti-GP2 IgA and IgG antibodies as novel serological parameters in CD and assessed their association with distinct disease phenotypes. METHODS: Anti-GP2 and anti-Saccharomyces cerevisiae (ASCA) IgA and IgG were detected by ELISA employing recombinant human GP2 and phosphopeptidomannan, respectively and PAB by indirect immunofluorescence (IIF) in 271 sera, 169 with CD and 102 with ulcerative colitis (UC). As healthy controls 160 adult blood donors and 65 children were included. RESULTS: Anti-GP2 IgG and/or IgA were more prevalent in CD (51/169, 30.2%) than in UC (9/102, 8.9%) patients and in controls (9/225, 4%) (p < 0.001 respectively). ASCA IgG and/or IgA were present in 60/169 (35.5%) in CD and in 7/102 (6.9%) in UC patients (p < 0.001). CD patients with ileocolonic location (L3) showed a significantly higher prevalence of anti-GP2 and ASCA IgA and/or IgG (40/113 and 48/113, respectively; p < 0.05 for both comparisons), whereas CD patients with colonic location (L2) revealed a significantly diminished prevalence for these autoantibody specificities (2/32 and 5/32, respectively, p < 0.05 for both). Anti-GP2 IgG were significantly more prevalent in CD patients with stricturing behaviour (B2) and perianal disease (7/11, p < 0.02) and less prevalent in those with penetrating behaviour (B3) and perianal disease (4/31, p < 0.05). The occurrence of anti-GP2 IgA and/or IgG was significantly more prevalent in CD patients with age at diagnosis of ≤16 years (16/31, p < 0.009). Prevalence of one or more anti-GP2 or ASCA IgA and/or IgG was significantly higher in L3, B2, and A1 and lower in L2 (68/113, 27/41, 23/31, 6/32; p < 0.04, respectively). CONCLUSIONS: Anti-GP2 IgG and IgA, constituting novel CD specific autoantibodies, appear to be associated with distinct disease phenotypes identifying patients at a younger age, with ileocolonic location, and stricturing behaviour with perianal disease.

Pre-treatment with Bifidobacterium breve UCC2003 modulates Citrobacter rodentium-induced colonic inflammation and organ specificity.

Citrobacter rodentium, which colonizes the gut mucosa via formation of attaching and effacing (A/E) lesions, causes transmissible colonic hyperplasia. The aim of this study was to evaluate whether prophylactic treatment with Bifidobacterium breve UCC2003 can improve the outcome of C. rodentium infection. Six-week-old albino C57BL/6 mice were pre-treated for 3 days with B. breve, challenged with bioluminescent C. rodentium and administered B. breve or PBS-C for 8 days post-infection; control mice were either administered B. breve and mock-infected with PBS, or mock-treated with PBS-C and mock-infected with PBS. C. rodentium colonization was monitored by bacterial enumeration from faeces and by a combination of both 2D bioluminescence imaging (BLI) and composite 3D diffuse light imaging tomography with µCT imaging (DLIT-µCT). At day 8 post-infection, colons were removed and assessed for crypt hyperplasia, histology by light microscopy, bacterial colonization by immunofluorescence, and A/E lesion formation by electron microscopy. Prophylactic administration of B. breve did not prevent C. rodentium colonization or A/E lesion formation. However, this treatment did alter C. rodentium distribution within the large intestine and significantly reduced colonic crypt hyperplasia at the peak of bacterial infection. These results show that B. breve could not competitively exclude C. rodentium, but reduced pathogen-induced colonic inflammation.

Effects of ischemia and reperfusion on production of nitrotyrosine, activation of eosinophils, and apoptosis in the large colonic mucosa of horses.

OBJECTIVE: To assess the effects of ischemia and reperfusion on indicators of oxidative stress, activation of eosinophils, and apoptosis in the large colonic mucosa of horses. ANIMALS: 40 horses. PROCEDURES: In 1 or two 20-cm-long segments of the pelvic flexure, ischemia was induced for 1 or 2 hours followed by no reperfusion or 30 minutes and 18 hours of reperfusion in anesthetized horses. Mucosal specimens were collected before (controls; n = 20 horses) and after each period of ischemia, and full-thickness tissue samples were collected after each period of reperfusion. Sections of colonic tissues were stained for histomorphometric analysis or assessment of eosinophil accumulation. Nitrotyrosine was identified immunohistochemically, and severity of apoptosis was determined via the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. RESULTS: Numbers of mucosal eosinophils were similar before induction of ischemia, after ischemia, and after ischemia-reperfusion. Eosinophil nitrotyrosine production increased significantly during ischemia and continued through 30 minutes of reperfusion; production was decreased at 18 hours of reperfusion but remained greater than that of the controls. In other leukocytes, nitrotyrosine generation peaked at 1 hour of ischemia and again at 18 hours of reperfusion. Compared with control findings, epithelial apoptosis increased gradually at 1 through 2 hours of ischemia with no further progression after reperfusion. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that resident eosinophils in the large colon of horses react to mucosal injury from ischemia and reperfusion and may undergo oxidative stress under those conditions. Epithelial apoptosis could contribute to tissue damage.

The humoral response after laparoscopic versus open colorectal surgery: a meta-analysis.

BACKGROUND: The local and systemic humoral response after colorectal surgery is thought to affect postoperative recovery. It is commonly claimed that laparoscopic surgery elicits a diminished inflammatory response than equivalent open surgery. Despite these claims, the evidence is conflicting. Therefore, we aimed to systematically review the results from randomized controlled clinical trials comparing the humoral response associated with laparoscopic versus open colorectal surgery. MATERIALS AND METHODS: A high-sensitivity search was conducted independently by two of the authors with no language restriction. Studies were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), Cochrane Library, Medline (January 1966 to January 2009), PubMed (1950 to January 2009), and Embase (1947 to January 2009). Relevant meeting abstracts and reference lists were manually searched. Data analysis was performed using Review Manager ver. 5.0. RESULTS: Thirteen randomized controlled trials were included. Meta-analysis demonstrated a significantly higher serum IL-6 on d 1 after open colorectal resection for neoplasia (n = 97) compared with laparoscopic resection (n = 76, P = 0.0008) without significant heterogeneity. Data for plasma IL-6 were heterogeneous, with no apparent difference between groups. No other significant differences were identified, and there were not enough data on local peritoneal humoral factors to allow meta-analysis. CONCLUSION: Open colorectal resection for neoplasia is associated with higher postoperative serum levels of IL-6 on d 1 than equivalent laparoscopic surgery. The aetiology and clinical significance of this finding is uncertain, and further studies are required to elucidate any differences in the local humoral response which may be more clinically relevant in surgery for this indication.