Combined Histological and Endoscopic Endpoints at Post-induction Lack Additional Prognostic Value Compared with Endoscopic Improvement Alone in Ulcerative Colitis: A Post hoc Analysis of the VARSITY study.

BACKGROUND AND AIMS: Evaluating histological outcomes in ulcerative colitis [UC] has become common in recent clinical trials. In this study, we explored the additional value of the combined endpoint of histo-endoscopic mucosal improvement [HEMI] compared with endoscopic improvement [EI] at post-induction [Week 14] and post-maintenance [1 year]. METHODS: This post hoc analysis included 620 UC participants with available data from the VARSITY trial. Participants achieving post-induction and post-maintenance HEMI [Mayo endoscopic subscore ≤1 and Geboes score <3.2] were compared across clinical outcomes, patient-reported outcomes [PROs], and inflammatory markers. Univariate analyses were performed to identify variables associated with the outcome of interest. Multivariate analyses included covariates with a p <0.05 on univariate analyses. RESULTS: Among the 468 patients with 1-year data available, a total of 166 [35.5%] attained HEMI and 209 [44.7%] attained EI at post-induction. No difference in achievement of clinical remission [CR] at 1 year was observed among those who attained post-induction HEMI vs EI (121/166 [72.9%] vs 147/209 [70.3%], p = 0.903). Similar findings were observed for the outcome of 1-year treatment failure (45/166 [27.1%] vs 55/209 [26.3%], p = 0.781). Patients who achieved HEMI at post-induction had lower total and partial Mayo scores and had the largest improvement from baseline. Faecal calprotectin and C-reactive protein [CRP] were also significantly lower among HEMI achievers at post-induction [p <0.001]. Similar findings were observed at post-maintenance. CONCLUSIONS: In this post hoc analysis, at post-induction, HEMI did not demonstrate additional prognostic value in predicting 1-year outcomes over EI. However, HEMI was associated with lower clinical disease activity at post-induction and at 1 year compared with endoscopic or histological outcomes in isolation.

End of induction patient reported outcomes predict clinical remission and endoscopic improvement with vedolizumab and adalimumab in ulcerative colitis.

BACKGROUND: Patient-reported outcomes (PROs) are increasingly emphasized as endpoints in clinical trials of ulcerative colitis (UC). However, the prognostic value of early improvement in PROs for long-term outcomes remains unclear. METHODS: This was a post-hoc analysis of 611 vedolizumab-treated or adalimumab-treated patients in the VARSITY trial (Clinicaltrial.gov: NCT02497469). Stool frequency (SF) and rectal bleeding score (RBS) as reported in the Mayo score at post-induction (week 6 and 14) was assessed for their association with one-year endoscopic improvement (EI), defined as Mayo endoscopic subscore <2; histo-endoscopic mucosal improvement (HEMI), defined as EI and Geboes highest grade <3.2, clinical remission (CR), defined as total Mayo score ≤2; and PRO-2 remission, defined as RBS of 0 and SF ≤1. Multivariable logistic regression models adjusted for confounders assessed the relationships between post-induction PROs and outcomes of interest at one-year. RESULTS: Patients with severe SF at week 6 were significantly less likely to achieve one-year EI compared to those with non-severe SF [aOR 0.40 (95% CI: 0.24-0.68), p < .001]. Absence of rectal bleeding at week 6 was associated with greater odds of achieving EI at one-year [aOR 2.21 (95% CI: 1.58-3.09), p < .001]. These findings were consistent across comparisons at week 14. Similar findings were observed for the outcomes of one-year HEMI, CR and PRO-2 remission. No difference was observed between the modified partial Mayo score and modified PRO-2 score. CONCLUSIONS: Post-induction PROs strongly predict the odds of CR and EI in UC and simplified evaluations can be used to assess early response to UC therapies.

Potential clinical complications of Orise™ gel use, a new submucosal lifting agent: experience from a tertiary care center and review of the literature.

Background: Endoscopic mucosal resection (EMR) involves forming a fluid cushion in the submucosal area with a lifting agent, followed by superficial resection. Orise™ gel is one of the commonly used lifting agents for EMR. We present a case series and literature review that analyzes the characteristic histopathological findings and clinical implications observed where Orise™ gel was used before EMR. Methods: Colon resection specimens and prior EMR specimens where Orise™ gel was used were reviewed for patients undergoing EMR between January 2018 and December 2020. The literature review included relevant studies from the Medline and Cochrane databases from January 2018 to December 2020. Results: A total of 12 colon polyp EMRs using Orise gel were performed during the study period. Seven patients (58.34%) underwent surgical resection. Histological examination revealed that, after the EMR procedure, the Orise™ gel material changed its morphological characteristics over time from a basophilic (bluish) non-inflamed pattern to an eosinophilic (pink) type pattern, eliciting a foreign body reaction. The endoscopic appearance and examination of the excised specimens weeks after injection gave the impression of a mass in some cases. The material was also present transmurally and in some cases in the peri-intestinal adipose tissue. Conclusions: It was observed that Orise™ gel use elicits a foreign body-type granulomatous reaction. This potential side effect may lead to overdiagnosis of a mass/lesion and unnecessary surgical interventions. This case series and review of the literature aims to increase awareness of the changes caused by Orise™ gel in the gastrointestinal tract.

Risk factors for local recurrence of large gastrointestinal lesions after endoscopic mucosal resection.

BACKGROUND: Endoscopic mucosal resection (EMR) is the primary treatment modality for superficial gastrointestinal mucosal lesions > 2 cm. However, the procedure carries some risk of complications including bleeding, perforation, and local recurrence. This study aimed to examine factors associated with EMR outcomes, especially in terms of local recurrence. METHODS: This study retrospectively evaluated patients who underwent EMR and full closure with prophylactic clips for upper and lower gastrointestinal lesions > 2 cm at Cleveland Clinic Florida, between January 2013 and December 2018 with follow-up endoscopic evaluation for recurrence. RESULTS: A total of 2031 endoscopic polypectomy cases were examined; 307 EMR procedures among 271 patients (52% were female, mean age 65.6 ± 11.1 years) who satisfied the inclusion criteria were included in the study. There were no perforations reported. The rate of post-polypectomy delayed bleeding was 1.6%, and the local recurrence rate in this cohort was 7.1%. Recurrent cases were successfully endoscopically managed. In the multivariate regression analysis, age > 70 years (OR = 3.20, 95% CI 1.17-8.76, p = .023), body mass index (OR = 1.12, 95% CI 1.03-1.23 p = .008), and lesion size ≥ 35 mm (OR = 11.51, 95% CI 3.54-37.40, p = < .001) were independent predictors for recurrence. CONCLUSIONS: Age > 70 years, increased lesion size, and obesity were found to be independent predictors of local recurrence among EMR procedures for gastrointestinal lesions > 2 cm. However, there is a need for larger-scale studies on this topic.

Ustekinumab does not increase risk of new or recurrent cancer in inflammatory bowel disease patients with prior malignancy.

BACKGROUND AND AIM: There is limited data on the rate of new or recurrent cancer in patients with inflammatory bowel disease (IBD) and a history of prior or current malignancy who are initiated on biologic therapies. Furthermore, there is no data on this topic in patients using ustekinumab. METHODS: The retrospective study included 341 patients with IBD and a history of cancer who were subsequently treated with vedolizumab (VDZ; n = 34), ustekinumab (USK; n = 27), tumor necrosis factor α antagonists (anti-TNF; n = 99), or had no immunosuppressive therapy (control; n = 181). Cox proportional hazard models were developed to determine the independent effect of post-cancer immunosuppressive treatment on the occurrence of incident cancer. RESULTS: Over a median of 5.2 person-years of follow up, cancer recurrence occurred in only one patient on anti-TNF, while new cancers developed in one patient on VDZ, three patients on USK, and six patients on anti-TNF, corresponding to cancer rates of 0.4, 1.8, and 0.7 per 100 person-years, respectively. The rate of incident cancer in control patients was 2.4 per 100 person-years and included 18 new and 9 recurrent cancers. Compared with controls, a stepwise Cox proportional hazards model adjusting for significant covariates found no increased risk of incident cancer in patients receiving post-malignancy treatment with USK (hazard ratio [HR] 0.88; 95% confidence interval [CI] 0.25-3.03), VDZ (HR 0.18; 95% CI 0.03-1.35), or anti-TNF (HR 0.47; 95% CI 0.20-1.12). CONCLUSION: Use of biologic therapy in IBD patients with a previous history of malignancy was not associated with an increased risk of new or recurrent cancer.

Pathogenetic mechanisms of nonalcoholic fatty liver disease and inhibition of the inflammasome as a new therapeutic target.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its incidence is increasing. Nonalcoholic steatohepatitis (NASH), the progressive form of the disease, can lead to end-stage liver disease. The pathogenesis of the disease is not fully understood, and there is currently no specific treatment. Therefore, an effective and reliable treatment modality is needed. In recent years, the inflammasome has been shown to play a vital role in many stages of NAFLD pathogenesis. In particular, the detection, by toll-like receptors, of pathogen-associated molecular patterns induced by the gut-liver axis triggers the formation of the NLRP3 (NLR family pyrin domain-containing protein 3) inflammasome. Stimulation of damage-associated molecular patterns also activates the NLRP3 inflammasome. The activated inflammasome has caspase-1 activity, which leads to the release of interleukin (IL)-1 and IL-18 and formation of pores in the cell wall. This process spreads the inflammatory process to the outside of the cell and induces inflammatory cell death (pyroptosis). Subsequent progression of the inflammatory process leads to fibrosis. Recent evidence suggests that the NLRP3 inflammasome may be a potential target for the treatment of NASH. The discovery of specific NLRP3 inflammasome blockers in recent years and evidence of their positive effects in experimental models support this therapeutic approach. In this article, we discuss recent evidence on the pathogenesis of NAFLD, the role of the inflammasome in the pathogenesis of NAFLD, and the potential effects of inhibition of the inflammasome.

Clinical and Endoscopic Predictors of Hydrostatic Balloon Dilation Failure for Post-Bariatric Anastomotic Stricture Treatment.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) patients can develop anastomotic strictures. The initial management relies on endoscopic hydrostatic balloon dilation, but in a subset of patients, it may be unsuccessful despite several dilations, requiring a different treatment modality. We evaluated the factors associated with balloon dilation failure and need for revision surgery. METHODS: Retrospective analysis from patients presenting with a post-RYGB anastomotic stricture who underwent balloon dilation from 2005 to 2018 at Cleveland Clinic Florida and Cleveland Clinic Main Campus. Demographic, clinical, surgical, endoscopic, and post-procedural variables were collected. Univariate and multivariate analysis with odds ratio (OR) and 95% confidence interval (95% CI) calculation for factors associated to dilation failure was performed. RESULTS: Eighty-nine patients were included in the analysis. Population was predominantly white (85.4%) and female (87.6%), with mean age 46.4 years and followed for a mean of 97.4 months. All patients presented dysphagia, with mean stricture diameter of 7.7 mm and associated marginal ulcer in 69%. Successful dilation was achieved in 65 patients, while 24 patients had dilation failure and underwent revisional surgery. Multivariate analysis showed a higher risk of dilation failure if time from RYGB to first dilation was >3 months (OR 4.95, 1.29-19.04; p = 0.02), and if nausea/vomiting were present before first dilation (OR 4.37, 1.11-17.16; p = 0.03). One patient had a perforation after dilation and was treated surgically. CONCLUSIONS: Post-RYGB anastomotic strictures can be successfully treated with hydrostatic balloon dilation. However, patients with dilations performed > 3 months after initial RYGB and nausea/vomiting have an increased risk of dilation failure and need for further interventions.

Risk Factors Associated With Postendoscopic Mucosal Resection Bleeding in Patients With Cirrhosis: A Retrospective Multicenter Cohort Study.

BACKGROUND AND AIM: There is limited data regarding the safety of endoscopic mucosal resection (EMR) in the cirrhotic population. Our study aimed to evaluate the safety of colonoscopic EMR in cirrhosis. MATERIALS AND METHODS: This was a retrospective review of cirrhotics who underwent colonic EMR at 8 Cleveland Clinic Centers between January 1, 2006, and December 31, 2018. Patient data including polyp details and complications occurring within 30 days of the procedure were noted. Univariable and multivariable logistic regression analyses were conducted to find risk factors for post-EMR bleeding. RESULTS: A total of 238 patients who underwent EMR were included. There were 145 males (60.9%) and the mean age was 61.9±8.6 years. Immediate and delayed bleeding, and postpolypectomy syndrome rates were 9.2%, 5.8%, and 1.3%, respectively. Significant risk factors for postpolypectomy bleeding were: increased age (P=0.001), procedure duration >37 minutes (P=0.001), antiplatelet use within 5 days (P=0.023), and lesion diameter >15 mm (P=0.004). Multivariable analysis revealed independent predictors of procedure-related bleeding: age above 65 years [odds ratio (OR) 2.14, P=0.044], antiplatelet use within 5 days (OR 2.42, P=0.047), right colon polyp (OR 3.51, P=0.001), and lesion diameter >15 mm (OR 3.22, P=0.003). CONCLUSIONS: EMR in cirrhotics has an acceptable bleeding risk. Age above 65 years, right colon polyp, polyp size >15 mm, and use of antiplatelets within 5 days are independent risk factors for bleeding.

Early Detection of Hepatocellular Carcinoma Recurrence in the Posttransplant Population: A Comparison of RETREAT and Cleveland Clinic Florida Scoring System.

BACKGROUND: Liver transplantation (LT) for hepatocellular carcinoma (HCC) is curative in most cases; however, recurrence is observed in some patients. The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score is an externally validated scoring system for prediction of post-LT HCC recurrence. The Cleveland Clinic Florida Scoring System (CCFSS) is a potential new scoring system for prediction of HCC recurrence. Our study aimed to compare the RETREAT and CCFSS. METHODS: We conducted a retrospective cohort study of 52 adult patients with HCC who underwent LT at a tertiary care center. Mantel-Haenszel chi-square analyses were conducted to compare the RETREAT and CCFSS classifications for detecting HCC recurrence. RESULTS: A total of 52 patients underwent LT. The median follow-up period was 37 months. Four patients had post-LT HCC recurrence, with all recurrences occurring within 2 years of LT. The RETREAT score was better able to detect low, moderate, and high levels of risk (P < .001), compared to the CCFSS score (P = 0.480). Both risk scores had a sensitivity of 75%; the specificity of the RETREAT score was 95.8%, whereas the specificity of the CCFSS was 60.4%. Alpha-fetoprotein level at the time of LT was associated with HCC recurrence (P = .014). CONCLUSIONS: This is the first study to evaluate the CCFSS as a potential new scoring system to predict HCC recurrence after LT. The RETREAT score is more specific than the CCFSS. The incorporation of alpha-fetoprotein level at the time of LT improves the estimation of HCC recurrence in the post-LT period.

Hyperbaric Oxygen Therapy in Chronic Inflammatory Conditions of the Pouch.

BACKGROUND: Pouchitis can be a chronic complication of ileal pouch-anal anastomosis. We aimed to determine the efficacy and safety of hyperbaric oxygen therapy (HBOT) for chronic antibiotic-refractory pouchitis (CARP) and other inflammatory conditions of the pouch. METHODS: This was a retrospective case series of adults with inflammatory bowel disease (IBD) who underwent ileal pouch-anal anastomosis and then developed CARP and received HBOT between January 2015 and October 2019. A modified Pouchitis Disease Activity Index (mPDAI) score was used to quantify subjective symptoms (0-6) and endoscopic findings (0-6) before and after HBOT. RESULTS: A total of 46 patients were included, with 23 (50.0%) being males with a mean age of 43.6 ± 12.9 years. The median number of HBOT sessions was 30 (range 10-60). There was a significant reduction in the mean mPDAI symptom subscore from 3.19 to 1.91 after HBOT (P < 0.05). The pre- and post-HBOT mean mPDAI endoscopy subscores for the afferent limb were 2.31 ± 1.84 and 0.85 ± 1.28 (P = 0.006); for the pouch body, 2.34 ± 1.37 and 1.29 ± 1.38 (P < 0.001); and for the cuff, 1.93 ± 1.11 and 0.63 ± 1.12 (P < 0.001), respectively. Transient side effects included ear barotrauma in 5 patients (10.9%) and hyperbaric myopic vision changes in 5 patients (10.9%). CONCLUSIONS: Despite minor adverse events, HBOT was well tolerated in patients with CARP and significantly improved symptoms and endoscopic parameters.

Association of Complicated Diverticulitis With Development of De Novo Inflammatory Bowel Disease.

BACKGROUND: There has been a historic similarity in the epidemiology and pathophysiology of diverticular disease and inflammatory bowel disease (IBD). Because there are limited to no data on the role of diverticulitis as a potential risk factor for de novo IBD, we aimed to evaluate the role of diverticulitis and complicated diverticulitis as a potential predictor of IBD. METHODS: We performed a retrospective, single-center study including patients older than age 18 years who were diagnosed with diverticulitis from January 2012 until December 2018 without a prior diagnosis of IBD. These patients were then evaluated for development of IBD. Univariate and multivariate analyses were conducted to compare the characteristics and outcomes between patients who did or did not develop IBD. RESULTS: A total of 2770 patients were diagnosed with diverticulitis from 2012 until 2018. Of these patients, 17 were diagnosed with IBD, resulting in an incidence rate of 0.23% per patient-year. The incidence rate among patients who required surgery for diverticulitis was 0.44% per patient-year, and patients with complicated diverticulitis had an incidence rate of 0.91% per patient-year. Univariate analysis showed that the need for surgery related to diverticulitis (hazard ratio [HR], 6.27; P = 0.003) and complicated diverticulitis was associated with the development of IBD (HR, 14.71; P < 0.001). Multivariate analysis showed that complicated diverticulitis was the sole factor associated with IBD (HR, 10.34; P < 0.001). CONCLUSIONS: Patients with diverticulitis are at a higher risk of developing de novo IBD. This risk is highest in patients with complicated diverticulitis.

Utility and safety of balloon-assisted enteroscopy in patients with left ventricular assist devices: a retrospective multicenter study.

Objective and study aims Patients with left-ventricular assist devices (LVADs) have an increased risk of gastrointestinal bleeding, especially from the small bowel, often necessitating evaluation with balloon-assisted enteroscopy (BAE). Our study aimed to assess the periprocedural safety and utility of BAE for gastrointestinal bleeding in patients with LVADs. Patients and methods This was a multicenter retrospective cohort study of adults with LVADs who underwent BAE between January 2007 to December 2018. Results Thirty-four patients underwent a total of 46 BAEs (9 were single-balloon enteroscopies [SBEs] and 37 were double-balloon enteroscopies [DBEs]). Mean age of patients was 66.4 ±â€Š8.3 years. Patients tolerated anesthesia well, without complications. There were no complications from the BAE itself. One patient required repeat BAE due to a progressive drop in hemoglobin and another patient developed paroxysmal supraventricular tachycardia. One patient died within 72 hours of the procedure due to worsening of LVAD thrombosis. Diagnostic yields were 69.6 % for all procedures, 73.0 % for DBE and 55.6 % for SBE ( P  = 0.309). Therapeutic yields were 67.4 % overall: 73.0 % for DBE and 44.4 % for SBE ( P  = 0.102). In those that presented with overt gastrointestinal bleeding, DBE had a higher diagnostic yield compared to SBE (84.2 % vs. 42.9 %; P  = 0.057) and a significantly higher therapeutic yield (84.2 % vs. 28.6 %; p = 0.014). Conclusions This is the largest multicenter study of patients with LVADs who underwent DBE. BAE appears to be a safe and useful modality for the evaluation of gastrointestinal bleeding in these patients.

Abdominal Pain in a Patient With Diverted Bowel and Inflammatory Bowel Disease.

Patients with medically refractory inflammatory bowel disease may undergo total proctocolectomy with ileal pouch-anal anastomosis. However, fecal diversion is necessary in patients with pouch failure. We present a rare case of pyogenic liver abscess (PLA) in a patient with ulcerative colitis with a history of ileal pouch-anal anastomosis complicated by chronic pouchitis requiring fecal diversion via loop ileostomy. The PLA was managed with computed tomography-guided aspiration drainage and antibiotics, followed by permanent ileostomy and pouch excision to prevent recurrence of PLA. This is the first case report of PLA in a patient with ulcerative colitis with a long-standing history of diversion pouchitis.

Gemcitabine: A Review of Chemoresistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma, an exocrine tumor, is the most common type of cancer of the pancreas and one of the top five most prominent causes of cancer-associated mortality worldwide. The survival rate for pancreatic cancer is sadly less than 8%. The high fatality rate is partly related to late diagnosis and partly to the aggressive nature of malignant cells that disseminate to nearby tissues at an early stage of the disease, making treatment difficult. Available treatment choices consist of both medical and surgical: removal of the tumor, use of various medications like chemotherapeutic drugs and immunotherapeutic agents, radiation therapy, and targeted drug therapy. Since most patients suffer from advanced cancer at the time of diagnosis, chemotherapy becomes the primary therapeutic option in such cases. Drugs like Gemcitabine, Abraxane, FOLFIRINOX, and newer combination therapies are all effective in management, either curatively or palliatively. However, chemoresistance poses a significant challenge. Several factors, both intrinsic and acquired, are involved in drug resistance. Here, we review the mechanism of action of the first-line chemotherapy drugs in pancreatic cancer and various factors associated with cancer chemoresistance.

Correction: Lidocaine-Induced Systemic Toxicity: A Case Report and Review of Literature.

[This corrects the article DOI: 10.7759/cureus.1275.].

Colovesical Fistula: An Unusual Complication of Cytomegalovirus Colitis.

Cytomegalovirus (CMV) is a double-stranded DNA virus that is associated with clinically significant disease in patients with advanced immunosuppression, particularly those with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). End-organ disease with CMV is classically associated with a CD4 cell count less than 50 cells/microliter. CMV colitis is the second most common manifestation of end-organ disease in this patient population. CMV-associated enteric fistula is a rare complication that has been described in only a few case reports in the literature. These cases describe gastrocolic, enterocutaneous, enterocolic, rectovaginal, and colocutaneous fistulae. However, colovesical fistula has not been described previously. Here, we report the first case of CMV-associated colovesical fistula in a patient with HIV infection and AIDS.

Immune Reconstitution Inflammatory Syndrome Associated Thrombocytopenia in a Patient with Human Immunodeficiency Virus Infection: A Rare Hematological Manifestation.

Human immunodeficiency virus (HIV) associated thrombocytopenia was commonly encountered in the era prior to the advent of antiretroviral therapy (ART). With the widespread use of ART, its incidence has significantly declined. Immune reconstitution inflammatory syndrome (IRIS) is an immune dysregulation phenomenon that reveals itself clinically as paradoxical deterioration after the commencement of ART in HIV infected patients. It has a wide variety of clinical manifestations. However, hematologic involvement is rare. Here, we present a very rare case of IRIS associated thrombocytopenia. With this case we intend to create mindfulness of the possibility of IRIS being one of the explanations for thrombocytopenia.

Infective Endocarditis Presenting as Bilateral Orbital Cellulitis: An Unusual Case.

Orbital cellulitis is a severe and sight-threatening infection of orbital tissues posterior to the orbital septum. The most common causes of orbital cellulitis are rhinosinusitis, orbital trauma, and surgery. Infective endocarditis (IE) is a systemic infection that begins on cardiac valves and spreads by means of the bloodstream to peripheral organs. Septic emboli can spread to any organ including the eyes and can cause focal or diffuse ophthalmic infection. Ocular complications of IE classically include Roth's spots, subconjunctival hemorrhages, chorioretinitis, and endophthalmitis. IE as a cause of orbital cellulitis has been described by only one author in the literature. Here, we present a very rare case of bilateral orbital cellulitis caused by IE. Through this case, we aim to create awareness of the potential for serious ocular complications in IE and provide an overview of the management.