Sigmoid Biopsies Research Articles

P066 Serum amyloid A – A Novel Biomarker of Ulcerative Colitis Disease Activity

Abstract Background Despite recent advancements in the treatment of ulcerative colitis (UC), a substantial number of patients fail to achieve long-term remission. Persistent histological activity has been linked with poorer treatment outcomes. Histological remission is now an accepted treatment target; however there remains significant variability in the interpretation of UC histology. As such, there is a need for novel biomarker identification to aid assessment and ultimately predict disease relapse. Serum amyloid A (SAA) is an acute-phase protein, of which serum levels have shown promise as a biomarker in IBD1. This study aims to explore the utility of SAA levels in UC colonic tissue as a diagnostic biomarker for disease activity and progression. Methods Two cohorts were prospectively recruited, including healthy controls and UC patients. Sigmoid biopsies were collected and tissue explants generated. Tissue-conditioned media from these explants was collected and secreted SAA quantified using 54 V-plex ELISA. Demographic information, disease characteristics, endoscopic Mayo scores and disease progression were documented. Endoscopic remission was defined as a Mayo endoscopic sub-score ≤1. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent in follow-up period. P values <0.05 were considered significant in analyses. Results The two cohorts included 11 healthy controls and 16 UC patients (endoscopic remission n=6). Active UC patients demonstrated significantly higher SAA concentrations than healthy controls (p=0.0013) and those in endoscopic remission (p=0.02). There was no significant difference in SAA concentrations between healthy controls and UC patients in remission (p=NS). UC patients in the lowest SAA concentration quartile had a significantly longer time to disease progression (p=0.0462) (Figure 1). Conclusion Quantification of SAA secretion in IBD ex-plants has potential as a biomarker of UC activity and progression. Further investigation of SAA as a biomarker in IBD is warranted.

Diverticulosis is not associated with altered gut microbiota nor is it predictive of future diverticulitis: a population-based colonoscopy study

Background The etiopathogenesis of diverticular disease is unknown. Objective To compare the fecal and mucosa-associated microbiota between participants with and without diverticulosis and participants who later developed diverticulitis versus those that did not from a population-based study. Methods The PopCol study, conducted in Stockholm, Sweden, invited a random sample of 3556 adults to participate, of which 745 underwent colonoscopy. Overall, 130 participants (17.5%) had diverticulosis. 16S rRNA gene sequencing was conducted on available sigmoid biopsy samples from 529 and fecal samples from 251 individuals. We identified individuals who subsequently developed acute diverticulitis up to 13 years after sample collection. In a case-control design matching for gender, age (+/−5 years), smoking and antibiotic exposure, we compared taxonomic composition, richness and diversity of the microbiota between participants with or without diverticulosis, and between participants who later developed acute diverticulitis versus those who did not. Results No differences in microbiota richness or diversity were observed between participants with or without diverticulosis, nor for those who developed diverticulitis compared with those who did not. No bacterial taxa were significantly different between participants with diverticulosis compared with those without diverticulosis. Individuals who later developed acute diverticulitis (2.8%) had a higher abundance of genus Comamonas than those who did not (p = .027). Conclusions In a population-based cohort study the only significant difference was that those who later develop diverticulitis had more abundance of genus Comamonas. The significance of Comamonas is unclear, suggesting a limited role for the gut microbiota in the etiopathogenesis of diverticular disease.

P754 Beyond Paneth cell metaplasia: Small intestinal metaplasia of the sigmoid colon in patients with Inflammatory Bowel Disease

Abstract Background Paneth cells are normally found in the small intestine, and when found in the left colon, they represent Paneth cell metaplasia (PCM). This finding indicates a chronic inflammatory state and is seen in some patients with inflammatory bowel disease (IBD). However, small intestinal differentiation beyond PCM has not been reported. We report a broader range of small intestinal metaplasia in the sigmoid colon in patients with IBD, including loss of expression of the colonic marker SATB2, presence of a brush border and villous architecture, and gain of expression of the small intestinal markers CD10 and HepPar1. We perform a pilot study to investigate the frequency, staining patterns, and clinical correlates of this metaplastic phenomenon. Methods A database search for sigmoid biopsies for the words “Paneth cell metaplasia” from 2010-2018 returned 862 cases. The 100 most recent consecutive cases with a history of IBD were reviewed and confirmed to have PCM in non-neoplastic sigmoid biopsies in 96 cases. Of these, 94 blocks from 91 patients (age range 7-88, median age 43, 53% male, 74% ulcerative colitis (UC), 23% Crohn’s disease, 3% IBD) were on file. IHC staining for HepPar1, CD10, and SATB2 was performed on each case. Results Of the 94 cases, 13 (13.8%) had HepPar1 positivity, 5 (5.3%) had CD10 positivity, 2 (2.1%) had SATB2 loss, 1 (1.1%) had reduced SATB2 expression, and 2 showed villous architectural features. Extensive positivity for CD10 was seen in 3 (3.2%) cases, and one case showed all 3 IHC markers of small intestinal metaplasia. Of the CD10+ cases, there were 3 UC, 1 Crohn's, and 1 IBD (Table 1). The index case (sigmoid colon) showed a brush border (Figure 1) and intermixed small (Figure 2, red arrows) and large bowel (Figure 2, black arrows) differentiation. Conclusion A range of small intestinal differentiation may be seen in the left colon in IBD patients, including PCM, the presence of brush border, villous architecture, CD10 and HepPar1 positivity, and reduced or lost SATB2 expression. Since the frequency of HepPar1+>CD10+>SATB2 loss, there may be a sequence of small intestinal metaplasia, with PCM occurring first, and loss of SATB2 reflecting more advanced metaplasia. Previous studies suggest that SATB2 and HepPar1 are helpful in distinguishing between inflamed ileal pouch vs rectal cuff in patients with IBD, and that CD10 could be used to distinguish between ileum and colon in anastomoses, but our data refute these claims. SATB2 loss has been described in dysplastic lesions in patients with IBD, and thus these markers could serve as biomarkers of progression to dysplasia.

S2772 Subcutaneous Sweet Syndrome Successfully Treated With Ustekinumab in Patient With Ulcerative Colitis

Introduction: Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are well-established. Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is a reactive mucocutaneous manifestation of IBD presenting as erythematous papules/plauqes with associated fever and arthomyalgias. There is limited evidence regarding efficacy of Ustekinumab in management of EIMs of UC, particularly SS. Case Description/Methods: The patient is a 50-year-old woman with left-sided UC (Montreal classification E2) that previously failed several therapies, including mesalamine, azathioprine, infliximab, adalimumab, vedolizumab, and a fecal microbiota transplant trial. She presented with worsening abdominal pain, diarrhea/hematochezia, and bilateral lower extremity pain. She was febrile and tachycardic with tender, violaceous, and ulcerated subcutaneous nodules on the bilateral ankles with hemorrhagic bullae (FigureA). Labs revealed negative C. diff, elevated ESR/CRP, thrombocytosis, and borderline leukocytosis with neutrophilic predominance. Lower extremity MR imaging and bone biopsy revealed multifocal sterile osteomyelitis with adjacent abscess; skin biopsy demonstrated dense granulomatous/neutrophilic infiltrate in the deep dermis/subcutis without microorganisms, consistent with subcutaneous SS (FigureB). A restaging colonoscopy demonstrated severe proctosigmoid ulcerative colitis (FigureC). Given that the patient had failed several immunomodulators and biologic therapies, she was started on prednisone and Ustekinumab. Four months later, she reported complete resolution of her cutaneous SS off steroids and improving UC symptoms (less frequent and more formed stools, minimal hematochezia). Repeat MRI demonstrated resolution of the sterile osteomyelitis and abscess. Discussion: Our case highlights the novel use of Ustekinumab in the treatment of subcutaneous SS with sterile osteomyelitis in a patient with flaring UC. SS is a neutrophilic dermatosis that is a rare EIM of IBD, classically characterized by tender cutaneous lesions. There is limited evidence supporting the use of Ustekinumab in treating EIMs of CD, and a lack of data regarding its efficacy in treating EIMs of UC. Our case fills a major gap in the literature and highlights the clinical efficacy of Ustekinumab for SS and UC especially in patients that have a contraindication to, failed previous treatment with, or otherwise cannot tolerate corticosteroids and TNF-alpha antagonists.Figure 1.: 1A. Right lateral malleolus with 2.5 cm shallow erosion with slightly violaceous borders and central bright yellow fibrinous debris. There was slight atrophy of surrounding skin with mild edema and hyperpigmentation (left image). Left medial malleolus/dorsal foot with grouped irregular shallow ulcers with surrounding mild violaceous erythema (middle and right image). 1B. Left ankle biopsies showed mixed septal and lobular panniculitis with granulomatous and neutrophilic inflammation. Histologic sections show a mildly spongiotic epidermis with dense granulomatous and neutrophilic inflammatory infiltrate in the deep dermis and subcutis (left image). The inflammatory infiltrate, which consists of prominent neutrophils, histiocytes, and scattered lymphocytes, surrounds vascular and adnexal structures, as well as adipocyte lobules. Definitive features of vasculitis are not seen. PASd (periodic acid-Schiff-diastase), GMS (Grocott’s methenamine silver), Gram, and Fite staining fail to highlight microorganisms (right image). 1C. Colonoscopy demonstrated severe (Mayo Endoscopy Score 3) proctosigmoid ulcerative colitis to 30 cm (left image). Sigmoid biopsies showed significant immune cell infiltration with crypt architectural distortion concerning for severe chronic active colitis. No evidence of granulomas, dysplasia or cytomegalovirus (right image).

Expression of TRP Channels in Colonic Mucosa of IBS-D Patients and Its Correlation with the Severity of the Disease.

Aim Lots of researches have endeavored to elucidate the pathogenetic mechanism of visceral hypersensitivity in order to guide the therapy of diarrhea predominant-irritable bowel syndrome (IBS-D). Transient receptor potential (TRP) channels and their role in visceral nociception have been vastly investigated. We investigated the expression of TRP channels in IBS-D colonic biopsies and its correlation with the severity of the disease. Methods Sigmoid biopsies were obtained from 34 IBS-D patients and 28 healthy controls (HCs). IBS-D was diagnosed according to Rome IV criteria. Their clinical parameters were assessed through questionnaires. Expression of TRPV1, TRPV4, TRPA1, TRPM2, and TRPM8 was evaluated with immunohistology staining. Results Expression levels of TRPV1, TRPV4, and TRPA1 in the colonic mucosa of IBS-D patients were significantly higher than those in HCs (p < 0.05), while there was no obvious difference of TRPM2 and TRPM8 expression between IBS-D patients and HCs. In addition, the expression levels of TRPV1 and TRPA1, but TRPV4, in the colonic mucosa correlated positively with the severity of diseases (r = 0.6303 and 0.4506, respectively, p < 0.05). Conclusions Expression of TRPV1, TRPA1, and TRPV4 in the colonic mucosa was enhanced in IBS-D patients compared with HCs with the former two correlated with the severity of the disease. TRP channels might be promising biomarkers in the diagnosis and estimate of the severity in IBS-D.

Eosinophilic Myenteric Ganglionitis with Degenerative Leiomyopathy

Background: Chronic intestinal pseudo-obstruction (CIPO) is an umbrella term for a range of different conditions characterized by repetitive episodes or continuous symptoms and signs of bowel obstruction, including radiographic evidence of dilated intestines and air-fluid levels, due to impaired propulsion in the absence of an anatomical occluding lesion. It is a diagnostic challenge and can mimic Hirschsprung's disease. Clinical Description: A 10-month-old boy presented with a history of recurrent episodes of constipation since the age of 6.5 months. The first two had resolved with symptomatic treatment. The third had been associated with bilious vomiting and required exploratory laparotomy. He was referred to us when there was no symptomatic improvement. The child underwent extensive workup that included a review of earlier investigations (contrast-enhanced computerized tomography abdomen, barium enema, and sigmoid biopsy) as well as upper gastrointestinal endoscopy, workup for secondary CIPO, esophageal and antroduodenal manometry, genetic studies, for primary CIPO. A laparotomy with concurrent adhesionolysis, appendectomy, gastrostomy, and ileostomy was undertaken, which included full-thickness biopsies at multiple sites. This revealed both degenerative leiomyopathy and eosinophilic myenteric ganglionitis (EMG). Known associations of CIPO, an underactive bladder, and sinus arrhythmias were also detected. Management: The infant was provided with supportive therapy. A trial of steroids was given for the EMG. The child had multiple bad prognostic factors and also protracted multiple nosocomial infections. He succumbed to his illness and complications after 40 days of hospitalization. Conclusion: The combination of EMG and degenerative leiomyopathy has not been reported in CIPO before.

Colorectal adenocarcinoma with enteroblastic differentiation: diagnostic challenges of a rare case encountered in clinical practice

Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of colonic adenocarcinoma characterized by increased α-fetoprotein (AFP) production and the expression of at least one enteroblastic marker including AFP, glypican 3 (GPC3), or Spalt like transcription factor 4 (SALL4). We report a case of a 26-year-old female who presented with low back pain and constipation which persisted despite supportive measures. Imaging revealed multiple liver lesions and enlarged retroperitoneal nodes. Tumor markers including AFP were markedly elevated. On biopsy, samples from the liver revealed infiltrating glands lined by columnar-type epithelium with mostly eosinophilic granular to focally clear cytoplasm. By immunohistochemistry, the tumor showed immunoreactivity with AFP, hepatocyte antigen, GPC3, SALL4, CDX2, SATB2, and cytokeratin 20. A colonoscopy performed subsequently revealed a mass in the sigmoid colon and biopsy of this mass revealed a similar histology as that seen in the liver. A diagnosis of CAED was made, following the results of gene expression profiling by the tumor with next-generation sequencing which identified pathogenic variants in MUTYH, TP53, and KDM6A genes and therefore supported its colonic origin. Cases such as this underscores the use of ancillary diagnostic techniques in arriving at the correct diagnosis in lesions with overlapping clinicopathologic characteristics.

P071 Intestinal CD8+ T cell exhaustion is linked to disease activity in ulcerative colitis

Abstract Background The immune pathogenesis of ulcerative colitis (UC) has been linked to imbalanced CD4+ T-cell responses while the contribution of CD8+ T cells is less well characterized. Chronically activated CD8+ T cells may become dysfunctional and acquire an exhausted phenotype during chronic viral infection or cancer. Recently, exhausted T cell (Tex) signatures have been proposed as a potential prognostic marker in autoimmune diseases. We therefore set out to characterize features of CD8+ T cell exhaustion in UC patients in more detail. Methods Lymphocytes were isolated from peripheral blood and sigmoid biopsies of UC patients in remission (n = 9) and active disease (n = 20). Cytokine production and expression of exhaustion-associated markers were analyzed ex vivo by flow cytometry. Results were correlated with disease activity (Mayo Score) and mucosal inflammation (assessed endoscopically and histologically [Nancy Score]). To further analyze the role of CD8+ T cells within the intestinal tissue microenvironment, Imaging Mass Cytometry (IMC) was applied on sigma biopsies (n= 21). Results Analysis of CD8+ Tex marker expression and functionality did not reveal major differences between peripheral blood lymphocytes isolated from UC patients with either active disease or remission as well as healthy controls. In contrast, in the sigmoid colon of patients with active UC, CD8+ T cell numbers were strongly increased. Moreover, expression of exhaustion markers was significantly increased in intestinal CD8+ T cells during active disease compared to remission. These cells also displayed dysfunctional cytokine profile patterns, as assessed by an established functional exhaustion score. This phenotype also closely correlated with clinical, endoscopic and histological markers of UC disease activity. The findings were confirmed by IMC, which revealed the presence of several clusters of CD8+ T cells with an exhaustion signature in inflamed colonic tissues. Conclusion Our findings indicate that inflammation in the intestines of UC patients is associated with the induction of CD8+ T-cell responses that phenotypically and functionally resemble Tex. The functional relevance, prognostic value and therapeutic relevance of these exhausted CD8+ T cell signatures in UC need to be analyzed in future studies.

Age-Related Decrease in Abdominal Pain and Associated Structural- and Functional Mechanisms: An Exploratory Study in Healthy Individuals and Irritable Bowel Syndrome Patients.

Introduction: The world population is ageing, resulting in increased prevalence of age-related comorbidities and healthcare costs. Limited data are available on intestinal health in elderly populations. Structural and functional changes, including altered visceroperception, may lead to altered bowel habits and abdominal symptoms in healthy individuals and irritable bowel syndrome (IBS) patients. Our aim was to explore age-related changes in gastrointestinal symptoms and underlying mechanisms. Methods: In total, 780 subjects (IBS patients n = 463, healthy subjects n = 317) from two separate studies were included. Subjects were divided into different age groups ranging from young adult to elderly. Demographics and gastrointestinal symptom scores were collected from all participants using validated questionnaires. A subset of 233 IBS patients and 103 controls underwent a rectal barostat procedure to assess visceral hypersensitivity. Sigmoid biopsies were obtained from 10 healthy young adults and 10 healthy elderly. Expression of the visceral pain-associated receptors transient receptor potential (TRP) Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) genes were investigated by quantitative RT-PCR and immunofluorescence. Results: Both elderly IBS and healthy individuals showed significantly lower scores for abdominal pain (p < 0.001) and indigestion (p < 0.05) as compared to respective young adults. Visceral hypersensitivity was less common in elderly than young IBS patients (p < 0.001). Relative TRPA1 gene transcription, as well as TRPA1 and TRPV1 immunoreactivity were significantly lower in healthy elderly versus healthy young adults (p < 0.05). Conclusions: Our findings show an age-related decrease in abdominal pain perception. This may in part be related to decreased TRPA1 and/or TRPV1 receptor expression. Further studies are needed to reveal precise underlying mechanisms and the associations with intestinal health.

S2431 Ulcerative Colitis Flare-Ups Following mRNA COVID-19 Vaccination

Introduction: Ulcerative colitis (UC) is an autoimmune disease commonly managed with immunosuppressants. However, its put UC patients at a higher risk for infections. Therefore, vaccination is an important part of management. Messenger RNA (mRNA) vaccine is a new type of vaccine only widely used against COVID-19. The effect of mRNA vaccines on UC patients on immunomodulatory treatement is relatively unknown. Here, we present the first case of UC flare-up after receiving the SARS-CoV-2 mRNA vaccine. Case description/methods: A 36-year-old female with past medical history of ulcerative colitis, autoimmune pancreatitis presented with intermittent lower abdominal pain and diarrhea for 2 weeks with fever for 1 day. Her last flare-up was 3 years ago before she was put on Tofacitinib. She never required hospitalization. Her symptoms started the second day after she received the second dose of Pfizer COVID-19 vaccine. She had daily 5-10 times of non-bloody diarrhea and abdominal cramps. Her symptoms subsided after 7 days of initial onset. On day 11, she started to have daily up to 15 times bloody bowel movements, along with nausea, vomiting, unable to maintain oral intake. Day 17 after vaccination, patient went to ED after fever of 100.5F. On presentation, she is afebrile, WBC 11.9, CRP 61.8, calprotectin 1840, Clostridioides difficile negative, GI Panel negative. CT showed severe colitis involving the left colon from splenic flexure to rectum. Colonoscopy showed erythematous, granular, hemorrhagic, and ulcerated mucosa in the entire examined colon. Terminal ileum, cecum, ascending, transverse, descending, sigmoid and rectum biopsies were negative for CMV, showed chronic active colitis. Patient received intravenous Methylprednisolone, then transited to oral Prednisone taper and resumed her Tofacitinib. Her symptoms gradually improved. Discussion: To our best knowledge, no report has shown the association of mRNA vaccine and UC flare-up. In general, non-live vaccines are safe for UC patients regardless of immunosuppressants usage. Live vaccines are also contraindicated Tofacitinib users like our patient. In the Pfizer COVID-19 vaccine trial, patients on immunosuppressive therapy were excluded. Given the temporal relationship between the vaccine and her flare-up in the setting of long-term remission history, we are concerned that the stress induced by the mRNA vaccine may increase the risk of flare-up. More studies need to be done to evaluate the safety profile of mRNA vaccine for UC patients on immunosuppressants.Figure 1.: A: Nodular mucosa in second portion of duodenum. B: Multiple ulcers in terminal ileum. C and D: 1.7 cm segment of terminal ileum circumferential bowel wall thickening with mucosal hyperenhancement and submucosal edema.

26118 Cutaneous Crohn masquerading as hidradenitis suppurativa

A 20-year-old female presented for possible hidradenitis suppurativa. She had an itchy, painful lesion on her labia majora for >2 years, with flares every few weeks. Physical examination was significant for hyperpigmented and erythematous plaques with fissuring of the labia majora and perianal region. She also reported constipation and abdominal pain but denied bloody stools. Previously worked up by pediatric gastroenterology (GI) 2 years prior for a 15-lb unintentional weight loss and constipation. Constipation had been ongoing for >10 years. Esophagogastroduodenoscopy, colonoscopy, and CT enterography were unremarkable other than anal papillomas. On physical examination, she had hemorrhoids, rectal fissures, and labial swelling. Inflammatory bowel disease (IBD) was ruled out by GI. She was prescribed polyethylene-glycol-3350 by GI for constipation. General surgery also excised the anal papillomas. Based on history and clinical exam, we were concerned for cutaneous Crohn disease. We started her on adalimumab, slow prednisone (40 mg) taper, and silver sulfadiazine. We also referred her back to GI for re-evaluation for IBD. Patient now reported blood associated with straining during bowel movements. GI noted perianal inflammation and repeated a colonoscopy, which showed a benign anal stricture, anorectal ulcers, and sigmoid ulcers. Rectal and sigmoid biopsies showed acute and chronic colitis with ulceration. She was formally diagnosed with Crohn disease. Patient reported full resolution of her cutaneous lesions over a 4-month period on adalimumab and the prednisone taper. Cutaneous genital and perianal fissures in the setting of gastrointestinal symptoms warrant evaluation for IBD even with prior negative workup.

Streptococcus suis and an Incidentally Diagnosed Metastatic Colon Cancer

Background: Streptococcus suis is a zoonotic infection known to cause meningitis and sepsis, in addition to several other rare manifestations. Infection with this organism is rare in the absence of pork ingestion or a handling history. Case presentation: The authors report the case of a 62-year-old male with no animal contact history, who presented with symptoms of urinary tract infection. It was his second infection over the course of 2 years. His urine culture was positive for Escherichia coli but his blood culture was positive for S. suis. Ultrasound of the abdomen ruled out underlying predisposing urinary pathology. However, it did show several heterogeneous liver masses with abnormal vascularity. A follow-up abdominal CT revealed a malignant neoplastic process involving the sigmoid colon with metastatic liver lesions. Colonoscopy demonstrated a fungating mass at the sigmoid colon and biopsies revealed a moderately differentiated adenocarcinoma. Conclusion: This case suggests the possibility of associated colon cancer in patients presenting with S. suis with no explicit history of animal or pork contact. It also proposes the existence of an association between colon cancer with Streptococcus species other than bovis.

Decreased number of colonic tuft cells in quiescent ulcerative colitis patients.

BackgroundColonic tuft cells are epithelial chemosensory cells involved in barrier integrity, modulation of inflammatory responses and gut homeostasis. Recent evidence indicates an involvement of tuft cells in ulcerative colitis pathogenesis, though mechanisms remain largely unknown.Here, we quantified the colonic tuft cell population in patients with quiescent ulcerative colitis as compared to patients without identified colonic disease (controls).MethodsIn this retrospective study, we obtained endoscopic colonic sigmoid biopsies from 14 patients with quiescent ulcerative colitis and from 17 controls. In a blinded central-reading design, we identified tuft cells by immunohistochemistry using a cyclooxygenase-1 antibody as a marker and performed a simple counting by visual inspection. Poisson regression was employed for statistics and results were adjusted for gender, age and smoking status.ResultsUlcerative colitis patients demonstrated a 55% reduced tuft cell count in colonic mucosa compared with the control group (95% confidence limit: range 31–71%, P = 0.0002). Ulcerative colitis patients had a mean tuft cells count of 46 tuft cells/mm2 (95% CI, 36–59), while controls demonstrated a mean of 104 tuft cells/mm2 (95% CI, 79–136). No interactions of other covariates, such as age, smoking status, total duration of ulcerative colitis disease and duration of clinical remission prior to study inclusion were detected between ulcerative colitis patients and controls.ConclusionQuiescent ulcerative colitis patients have a relatively low number of colonic tuft cells. Further studies are warranted to explore the potential involvement of tuft cells in ulcerative colitis pathogenesis.

S1710 Signet Ring Cell Mucinous Adenocarcinoma of the Colon Manifesting as Intermittent Hiccups

INTRODUCTION: Signet-ring cell mucinous adenocarcinoma is an unusual phenomenon, accounting for less than one percent of all colorectal cancers. In this case report, we describe the instance of an adult male whose symptoms of intermittent hiccups and right lower quadrant pain were actually bellwethers of an exceedingly rare and aggressive underlying malignant process. CASE DESCRIPTION/METHODS: A 59 year-old male with past medical history of vitiligo, cholelithiasis, and left inguinal hernia repair, presented to the Emergency Department (ED) with intermittent hiccups and abdominal discomfort. He described that these symptoms had progressed to nausea, vomiting, and a thirty-pound weight loss over a two-month period. Prior ED visits at two separate hospitals had diagnosed the patient with constipation and discharged him home. Upon admission, the patient was hemodynamically stable and labs were significant for a leukocytosis of 16.6 K/uL, potassium of 2.1 mmol/L, BUN/creatinine of 74/2.78 mg/dL, total bilirubin of 1.5 mg/dL, and a lipase of 843 U/L. Computed tomography (CT) of the abdomen and pelvis revealed a new small ascites collection and peritoneal carcinomatosis, suggestive of adenocarcinoma (Figure 1). CA 19-9 and CEA were elevated to 1477 U/mL and 4.9 ng/mL, respectively. Colonoscopy was performed, which identified friable mucosa at the sigmoid colon that was sent for biopsy (Figure 2). Based on histologic analysis, the patient was diagnosed with signet-ring cell mucinous adenocarcinoma of the sigmoid colon (Figure 3). Further work-up found evidence of metastases to the gallbladder and peritoneum, and the patient ultimately died from complications of his disease less than two months from the initial date of diagnosis. DISCUSSION: Signet-ring cell carcinoma (SRCC), with a reported incidence of 0.1% to 0.9% in the colon, is known for its distinctive “linitis plastica” appearance and aggressive disease pattern. In healthcare, we tend to attribute benign symptoms to common and less harmful diagnoses, often to the detriment of the patient. As with the patient described here, cases of signet-ring cell carcinoma are typically diagnosed at a more advanced tumor stage and in younger individuals compared to other colorectal cancers. SRCC most frequently metastasizes to the peritoneum and confers a particularly poor prognosis once it has done so, despite systemic or intraperitoneal chemotherapy. This case illustrates the need for critical thinking and thorough evaluation of even the most benign presenting symptoms.Figure 1.: CT Abdomen/Pelvis demonstrating peritoneal carcinomatosis.Figure 2.: Colonoscopy revealing erythema and friable mucosa at the sigmoid colon.Figure 3.: Sigmoid biopsy reveals pools of mucin dissecting through the lamina propria and submucosa. Within the mucin pools are malignant appearing epithelial cells, some showing signet ring morphology.

S2313 A Rare Presentation of an IL-12/23 Antagonist in Crohn’s Disease and Development of Sarcoidosis

INTRODUCTION: Anti-tumor necrosis factor (anti-TNF) therapy has been studied for use in inflammatory conditions such as IBD. There is a growing awareness of paradoxical reactions during treatment with this biologic agent. These can be defined as the development or exacerbation of a pathological condition which is triggered by the biologic agent being used. Commonly reported reactions include skin or joint manifestations, colitis or ileitis, or vasculitis. Paradoxically anti-TNF biologics have been reported to be useful to treat sarcoidosis and have been reported to cause sarcoidosis. Ustekinumab an IL-12/23 antagonist has been reported to cause sarcoidosis in 2 patients with psoriasis. We report the first case of a patient developing sarcoidosis during ustekinumab therapy for Crohn’s disease. CASE DESCRIPTION/METHODS: A 49 year-old female with history of breast carcinoma status-post mastectomy and adjuvant chemotherapy presented to clinic with abdominal pain and rectal bleeding. Prior colonoscopy on 6/26/17 only revealed pan-colonic diverticulosis. Colonoscopy on 10/12/18 revealed non-bleeding internal hemorrhoids, left-sided diverticulosis, sigmoid erythema/inflammation, and a normal terminal ileum. Sigmoid biopsies revealed chronic active colitis. She was started on Lialda with symptom resolution. The patient relapsed and was subsequently started on prednisone. Given the improvement with corticosteroids and suspicion of IBD, the patient was started on ustekinumab with a steroid taper and symptoms remained improved. Follow-up positron emission tomography scan for her breast cancer revealed uptake along the esophagus with development of mediastinal and bilateral hilar lymphadenopathy. Since there was concern for cancer, an EGD was performed, revealing only reflux esophagitis. Biopsies by pulmonology of her lymphadenopathy (EBUS) revealed noncaseating granulomatous sarcoidosis without evidence of malignancy. Ustekinumab was discontinued and the patient was restarted back on prednisone and Lialda with improvement. DISCUSSION: Side effects of ustekinumab, a monoclonal antibody to interleukin 12 and 23, can include cancers or serious infections. Our case describes a rare development of sarcoidosis in a Crohn’s Disease patient on ustekinumab therapy. The mechanism for this reaction remains unclear. The case does highlight the importance of knowing that all lymphadenopathy is not due to cancer even in patients with a cancer history and ustekinumab can cause sarcoidosis in patients with inflammatory bowel disease.

No distinct microbiome signature of irritable bowel syndrome found in a Swedish random population

ObjectiveThe ethiopathogenesis of irritable bowel syndrome (IBS) is unknown. While a link to the gut microbiome is postulated, the heterogeneity of the healthy gut makes it difficult to draw definitive...

Intestinal barrier function is maintained with aging \u2013 a comprehensive study in healthy subjects and irritable bowel syndrome patients

Animal studies have shown that intestinal barrier function is compromised with aging. We aimed to assess the effects of aging on intestinal barrier function in humans in vivo and ex vivo. In this cross-sectional study, healthy subjects and subjects with irritable bowel syndrome (IBS) of older (65–75 years) and young adult age (18–40 years) were compared. In vivo gastrointestinal site-specific permeability was assessed by a multi-sugar test, taking into account potential confounders. Sigmoid biopsies were collected from subgroups of healthy young adults and elderly for ex vivo Ussing chamber experiments, gene transcription of barrier-related genes and staining of junctional proteins. No significant differences between healthy young adults and elderly were found for small intestinal, colonic and whole gut permeability (P ≥ 0.142). In IBS patients, gastroduodenal and colonic permeability did not differ significantly (P ≥ 0.400), but small intestinal and whole gut permeability were higher in elderly versus young adults (P ≤ 0.009), mainly driven by the IBS-diarrhea subtype. Ussing chamber experiments with or without stressor (P ≥ 0.052), and relative expression of intestinal barrier-related genes (P ≥ 0.264) showed no significant differences between healthy elderly and young adults, as confirmed by immunofluorescent stainings. Overall, the functional capacity of the intestinal barrier is maintained in elderly.

P409 Endoscopic and histological activity is associated with non-response to biologic therapy in ulcerative colitis

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterised by a relapsing and remitting course. Biologic therapy in UC has a 30% rate of primary non-response (PNR) and a further 5% loss of response per year. Prognostic indicators of non-response include younger age and longer disease duration. Emerging evidence suggests that endoscopic and histological activity is associated with adverse outcomes such as clinical relapse and colectomy. However, the role of endoscopic or histological disease activity in predicting non-response to biologic therapy is unclear. We aim to investigate the association of endoscopic and histological activity with non-response to biologic therapy in UC. Methods Patients with UC treated with biologic therapy between 2014 and 2019 were studied. Baseline endoscopic disease activity was assessed using the Mayo endoscopic subscore from endoscopy performed prior to commencing biologic therapy. Patients who underwent colonoscopy 3–9 months after commencing biologic therapy were selected for histopathological review. Sigmoid biopsies were evaluated by an expert gastrointestinal pathologist. Histological parameters were scored on a 4-point scale, with blinding to clinical and endoscopic outcomes. Results Sixty-six patients were followed for a median of 16 months (IQR 6–30), 12 (18%) of whom did not respond to biologic therapy initially and 3 (6%) of whom lost response secondarily. Baseline endoscopic activity was associated with non-response (OR 6.1, 95% confidence interval 1.3 – 29.4, for every 1-point increase in the 4-point Mayo endoscopic subscore). 23 patients were identified for histopathological review. Four (17%) patients exhibited PNR. Baseline crypt atrophy was associated with PNR (p = 0.014) and baseline bifid crypts and crypt atrophy were associated with 52-week clinical relapse (p = 0.482 and p = 0.0497). Conclusion For patients with UC, endoscopic disease activity assessed prior to commencing biologic therapy has the potential to predict non-response to biologic therapy. In addition, specific histological parameters relating to crypt inflammation and crypt architecture may also predict non-response. Further prospective studies should be conducted to investigate the clinical utility of assessing endoscopic and histological disease activity prior to commencing biologic therapy.

The Impact of Pectin Supplementation on Intestinal Barrier Function in Healthy Young Adults and Healthy Elderly.

Intestinal barrier function is suggested to decrease with aging and may be improved by pectin intake. The aim of this study was to investigate the effects of four weeks pectin supplementation on gastrointestinal barrier function in vivo and ex vivo in different age groups. In a randomized, double-blind, placebo-controlled, parallel study, 52 healthy young adults (18–40 years) and 48 healthy elderly (65–75 years) received 15 g/day pectin or placebo for four weeks. Pre- and post-intervention, in vivo gastrointestinal permeability by a multisugar test, and defense capacity in mucosal samples were assessed. Sigmoid biopsies were collected post-intervention from subgroups for Ussing chamber experiments and gene transcription of barrier-related genes. Pectin intervention did not affect in vivo gastroduodenal, small intestinal, colonic, and whole gut permeability in young adults nor in elderly (p ≥ 0.130). Salivary and fecal sIgA and serum IgA were not significantly different between pectin versus placebo in both age groups (p ≥ 0.128). In both young adults and elderly, no differences in transepithelial electrical resistance and fluorescein flux (p ≥ 0.164) and relative expression of genes analyzed (p ≥ 0.222) were found between pectin versus placebo. In conclusion, intestinal barrier function was not affected by four weeks pectin supplementation neither in healthy young adults nor in healthy elderly.

HIV-1 is rarely detected in blood and colon myeloid cells during viral-suppressive antiretroviral therapy.

The aim of this study was to explore the contribution of blood and colon myeloid cells to HIV persistence during antiretroviral therapy (ART). Leukapheresis was collected from HIV-infected individuals with undetectable plasma viral load during ART (HIV + ART; n = 15) and viremics untreated (HIV+; n = 6). Rectal sigmoid biopsies were collected from n = 8 HIV+ART. Myeloid cells (total monocytes (Mo), CD16/CD16 Mo, CD1c dendritic cells) and CD4 T cells were isolated by magnetic-activated cell sorting (MACS) and/or fluorescence-activated cell sorting (FACS) from peripheral blood. Matched myeloid and CCR6CD4 T cells were isolated from blood and rectal biopsies by FACS. Levels of early (RU5 primers), late (Gag primers) and/or integrated HIV-DNA (Alu/HIV primers) were quantified by nested real-time PCR. Replication-competent HIV was amplified by co-culturing cells from HIV-positive individuals with CD3/CD28-activated CD4 T cells from uninfected donors. Early/late but not integrated HIV reverse transcripts were detected in blood myeloid subsets of four out of 10 HIV+ART; in contrast, integrated HIV-DNA was exclusively detected in CD4 T cells. In rectal biopsies, late HIV reverse transcripts were detected in myeloid cells and CCR6CD4 T cells from one out of eight and seven out of eight HIV+ART individuals, respectively. Replication-competent HIV was outgrown from CD4 T cells but not from myeloid of untreated/ART-treated HIV-positive individuals. In contrast to CD4 T cells, blood and colon myeloid cells carry detectable HIV only in a small fraction of HIV+ART individuals. This is consistent with the documented resistance of Mo to HIV infection and the rapid turnover of Mo-derived macrophages in the colon. Future assessment of multiple lymphoid and nonlymphoid tissues is required to include/exclude myeloid cells as relevant HIV reservoirs during ART.