Serum matrix metalloproteinase-7: a potential biomarker in patients with Lynch Syndrome.

BACKGROUND AND AIMS: The expression of tissue and serum matrix metalloproteinase-7 (MMP-7) was shown to be elevated both in colon cancer and dysplastic lesions. We aimed to evaluate, for the first time, its role as a diagnostic marker in Lynch syndrome (LS) carriers, a hereditary syndrome with predisposition to colon cancer. METHODS: This was a case control study. Baseline serum MMP-7 levels were determined by ELISA in 40 colon cancer patients, 62 LS-carriers and 60 healthy controls. Retrieved data from medical files included demographics, background diseases, clinical data regarding tumor characteristics and genetic data. We assessed the association of serum MMP-7 levels with different variables in the study cohort using linear regression model adjusted for potential confounders. RESULTS: In crude analysis, serum MMP-7 levels were significantly higher in colon cancer group compared to LS-carriers and controls [median (IQR) 4.1 ng/ml (2.7-6.0), 2.3 ng/ml (1.7-3.1), 2.5 ng/ml (1.5-3.7), respectively; p value - p < 0.001) while there was no difference between the two last groups (p value = 0.583). However, after adjusting for age and gender, LS-carriers' patients had 18% higher concentrations of serum MMP-7 compared to healthy controls (p value = 0.037), while colon cancer patients had 50% higher serum MMP-7 level in comparison to healthy controls (p value < 0.001). Additionally, age was positively associated with higher serum MMP-7 levels across all study groups (r = 0.67, p value < 0.001). In contrast, no correlation was observed between serum MMP-7 and either tumor staging and gene mutation. CONCLUSIONS: Age-adjusted serum MMP-7 levels in asymptomatic LS carriers are higher than its levels in healthy population. While in colon cancer, MMP-7 higher level probably reflects the tumor burden and may have a prognostic effect, its significance and clinical applicability as a biomarker for tumorigenesis in LS is less clear and should be elucidated.

Idiopathic Thrombocytopaenic Purpura associated with Inflammatory Bowel Disease: a multicentre ECCO CONFER case series.

BACKGROUND: Idiopathic thrombocytopaenic purpura [ITP] is an acquired haematological disorder with an incidence of 1-6 per 100 00/year. ITP and inflammatory bowel disease [IBD] comorbidity has been reported in the literature, but insights regarding the course, outcome and optimal management are limited by its rarity. The current study aimed to evaluate the clinical presentation and outcome of ITP in patients with IBD. METHODS: This multicentre retrospective case series was performed as part of the ECCO Collaborative Network of Exceptionally Rare case reports [CONFER] project. Cases of patients with ITP and IBD were collected by participating investigators. Clinical data were recorded in a standardized collection form. RESULTS: This report includes 32 patients with concurrent ITP and IBD: ten were females, and the median age was 32.0 years (interquartile range [IQR] 20.5-39.5). Fourteen patients had a diagnosis of Crohn's disease [CD] and the other 18 ulcerative colitis [UC]. The diagnosis of IBD preceded the ITP in 26 patients (median time between diagnoses was 7.0 years [IQR, 1.5-9.5]). Among those patients, 17 were in clinical remission at ITP diagnosis. Thirteen patients were treated with mesalamine, four with oral corticosteroids, one with rectal corticosteroids, two with azathioprine and five with anti-tumour necrosis factor agents. The median platelet count was 35 000/microliter [IQR, 10 000-70 000]. Eight patients had rectal bleeding, 13 had skin purpura, three had epistaxis, six had mucosal petechiae and 13 were asymptomatic. Regarding ITP treatment, 19 were treated with corticosteroids, one with anti-RhD immunoglobulin, 12 with intravenous immunoglobulins [IVIGs], four with thrombopoietin, three with rituximab and six patients eventually required splenectomy. Ten patients needed no treatment directed to the ITP. Three patients required colectomy during long-term follow-up, due to IBD or cancer but not to massive bleeding as a complication of ITP. One of eight patients who presented with rectal bleeding required splenectomy, and none required urgent colectomy. Two patients died during the follow-up, one of them due to bleeding complications located in the upper gastrointestinal tract. Median follow-up time was 6.5 years [IQR, 3-10]. With long-term follow-up, all patients had platelet counts above 50 000/microliter, and 24 were in IBD clinical remission. CONCLUSION: Most ITP cases in this series occurred after the IBD diagnosis and responded well to regular ITP treatment. The course of the ITP in the IBD patients followed an expected course, including response to medical therapy and low rates of splenectomy.

Characterization of blood-derived exosomal hTERT mRNA as a biomarker for colon cancer and Lynch syndrome.

Background: Human telomerase reverse transcriptase (hTERT)- mRNA was shown to be elevated in exosomes derived from the sera of a variety of hematological and solid cancer patients. We aimed to evaluate its role as a diagnostic marker in patients with newly diagnosed colon cancer and in hereditary syndromes with predisposition to colon cancer. Methods: hTERT -mRNA levels were determined in serum-derived exosomes from 88 patients with colon cancer, 71 Lynch-syndrome carriers with unknown active malignancies and 50 healthy controls. Data, including demographics, background diseases, clinical data regarding tumor characteristics and genetic data, were retrieved data from medical files. Results: Patients with colon cancer had both higher exosomal hTERT mRNA levels and a higher proportion of patients with positive exosomal hTERT mRNA than controls (29.5% vs. 4%, respectively, P values < 0.001). Within the cancer group, patients with a metastatic disease had higher levels of telomerase mRNA than non-metastatic disease patients, and these levels correlated with CEA levels. Likewise, Lynch syndrome carriers had a higher proportion of positive exosomal hTERT mRNA than controls (21.1% vs. 4%, respectively, P value 0.008) but only a trend towards higher exosomal hTERT mRNA levels. Higher telomerase mRNA levels were not correlated with the mutated gene. Conclusions: Exosomal serum hTERT -mRNA levels are associated with metastatic colon cancer and were also demonstrated in a subset of Lynch syndrome carriers. Its significance as a biomarker for developing malignancy should be elucidated.

The Utility of 18FDG-PET/CT in Diagnosing Fever of Unknown Origin: The Experience of a Large Tertiary Medical Center.

Fever of unknown origin (FUO) poses a diagnostic challenge, and 18-fluorodexoyglucose positron emission tomography with computed tomography (18FDG-PET/CT) may identify the source. We aimed to evaluate the diagnostic yield of 18FDG-PET/CT in the work-up of FUO. The records of patients admitted to Sheba Medical Center between January 2013 and January 2018 who underwent 18FDG-PET/CT for the evaluation of FUO were reviewed. Following examination of available medical test results, 18FDG-PET/CT findings were assessed to determine whether lesions identified proved diagnostic. Of 225 patients who underwent 18FDG-PET/CT for FUO work-up, 128 (57%) met inclusion criteria. Eighty (62.5%) were males; mean age was 59 ± 20.3 (range: 18-93). A final diagnosis was made in 95 (74%) patients. Of the 128 18FDG-PET/CT tests conducted for the workup of FUO, 61 (48%) were true positive, 26 (20%) false positive, 26 (20%) true negative, and 15 (12%) false negative. In a multivariate analysis, weight loss and anemia were independently associated with having a contributary results of 18FDG-PET/CT. The test yielded a sensitivity of 70%, specificity of 37%, positive predictive value of 70%, and negative predictive value of 37%. 18FDG-PET/CT is a valuable tool in the diagnostic workup of FUO. It proved effective in diagnosing almost half the patients, especially in those with anemia and weight loss.

Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination.

BACKGROUND: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. METHODS: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. FINDINGS: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. INTERPRETATION: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. FUNDING: none.

Evolution of Inflammatory Bowel Disease Research From a Bird's-Eye Perspective: A Text-Mining Analysis of Publication Trends and Topics.

BACKGROUND AND AIM: Inflammatory bowel disease (IBD) research is extensive and increasing, with topics varying and shifting foci over time. A comprehensive analysis of the trends in IBD publications may help us grasp knowledge gaps and map future areas of interest. The aim of our study was to create a map of IBD research for the last 25 years using computational text-mining techniques. METHODS: We retrieved all available MEDLINE/PubMed annual datasets between 1992 and 2016. We categorized article characteristics by using word combination and title match techniques. We also assigned country of origin for each article from the first author's affiliation. RESULTS: During the study period, 18,653 publications that appeared on PubMed were classified as IBD-related. The annual number of publications increased almost 4-fold (354 to 1361) during the study period. The United States had the highest total number of publications (n = 3179/16,358, 19.4%) and Denmark, Sweden, and Israel had the highest rate of publications per capita. There were 7986 articles successfully assigned with a main subject. Therapeutics, surgical treatment, and endoscopy were the 3 leading topics, with n = 2432/7986 (30%), 1707/7986 (21%), and 981/7986 (12%), respectively. When analyzing trends in topics over time, we found an increase in the proportion of articles on imaging (2.2% in 1992-1996 to 8% in 2012-2016) and a decrease in the proportion of articles on surgical treatment (30% in 1992-1996 to 19% in 2012-2016). CONCLUSIONS: There is steady increase in the number of IBD-related publications. Although the United States is a world leader in the number of IBD publications, Denmark, Sweden, and Israel publish the most per population size. Medical therapeutics is the most popular topic, yet there is a steady increase in publications devoted to imaging and monitoring.

Prediction of Recurrent Emergency Department Visits among Patients with Crohn's Disease: A Retrospective Study.

Patients with Crohn's disease (CD) are frequently subject to symptoms causing them to seek medical care in emergency departments (ED). Recurrent ED visits are frequent after initial discharge. We aimed to identify the characteristics of patients with Crohn's who tend to have recurrent visits to the ED. We created an electronic data repository of all patients with inflammatory bowel diseases who visited the ED in our tertiary medical center during the period 2012-2018. For this study, we retrieved consecutive Crohn's patients who presented with CD-related symptoms to the ED and were eventually discharged. Patients who returned to the ED in 7 and 30 days were compared with those who did not. Overall, 2299 patients visited our ED with complaints related to Crohn's disease exacerbation or complication. A total of 1259 (60% of the adult patients) were admitted for hospitalization. Of the 632 (33%) who were discharged from the ED, 53 (8.4%) and 110 (17.4%) re-visited the ED, in 7 and 30 days from discharge, respectively. In multivariable analysis, tachycardia (odds ratio (OR) = 2.19, 95% confidence interval (CI): 1.11-4.33, p value = 0.02), elevated alkaline phosphatase (OR = 2.09, 95% CI: 1.07-4.07, p value = 0.02), and hyponatremia (OR = 2.52, 95% CI: 1.24-5.10, p value = 0.01) were associated with revisiting the ED within 7 days. Tachycardia (OR 2.88 (95% CI 1.33-6.2)), anemia (OR 2.44 (95% CI 1.24-4.8)), and elevated alkaline phosphatase (OR 2.68 (95% CI 1.25-5.78)) were independently associated with ED returns in 30 days. Knowing these risk factors may assist in minimizing the burden of recurrent ED visits among patients with CD.

Novel bio-genetic predictors of response to biologic treatment in inflammatory bowel diseases.

Despite the evolving therapeutic armamentarium, the treatment of IBD patients remains challenging and many patients fail to respond to biologic agents. With the limited yield of clinical factors to predict the outcome of biologic treatments, studies have focused on identifying genetic alterations and circulating or tissue biomarkers to identify patients who are likely to respond to therapy. In this review, we examine the current knowledge and status of genetic, expression biomarkers, and microbiome predictors. The search for genetic predictors has yielded many genetic loci variants, but few were reproducible. Expression studies of putative biomarkers show promising results, especially with TREM1, oncostatin M and TNF biomarkers, but confirmatory studies are warranted. Finally, the microbiome is emerging as an important player with specific taxa and functional pathways differentially abundant and enriched in responders versus non-responders to certain biologics. Integrating different factors into a robust predictive model, which is both reproducible, accurate and affordable, remains the main challenge before these individualized strategies can reach clinical use.

Predictive factors for perioperative blood transfusions in laparoscopic colorectal surgery.

BACKGROUND: Allogeneic perioperative blood transfusion (PBT) has been associated with higher rates of postoperative complications in patients undergoing colorectal surgery and increased tumor recurrence in cancer patients. Our aim is to evaluate possible predictive factors for PBT, specifically, in patients undergoing laparoscopic colorectal surgery, in order to identify patients who could benefit from alternatives to allogenic PBT such as erythropoietin administration, autologous blood transfusion, and possibly preoperative blood transfusion. METHODS: Five hundred patients who underwent laparoscopic colorectal surgery between the years 2003 and 2011 were reviewed. Patient demographics and clinicopathologic variables were collected prospectively. Other clinical data were collected directly from the computerized records of the in-hospital blood bank. PBT was defined as transfusion of allogenic red blood cells during the day of operation or within the postoperative hospitalization. The associations between PBT and patient variables were assessed by univariate and multivariate analyses. RESULTS: Of the 500 patients, 134 patients (26.8 %) received PBT. Multivariate analysis revealed four preoperative variables as significant risk factors for PBT: preoperative hemoglobin (P = 0.001), lower rectal surgery (P = 0.009), Charlson comorbidity score (P = 0.001), and malignancy (P = 0.024). CONCLUSIONS: Preoperative Charlson score, hemoglobin level, carcinoma, and lower rectum pathologies were found to be independent risk factors for PBT in patients undergoing laparoscopic colorectal surgery. Evaluation of these risk factors prior to surgery may be helpful in selecting the patients who could benefit from possible alternatives to perioperative allogeneic blood transfusion and help constitute guidelines for a more responsible use of these alternatives.