NOD2 and Crohn's Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired.

Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.

NOD2 is the most relevant susceptibility gene for Crohn's disease. It is associated with the tructuring disease phenotype, ileal involvement, and an increased risk for surgery. NOD2 genetic variants emerge as promising candidates for developing precision medicine in Crohn's disease.

The Role of Capsule Endoscopy in the Diagnosis and Management of Small Bowel Tumors: A Narrative Review.

Small bowel tumors (SBT) are relatively rare, but have had a steadily increasing incidence in the last few decades. Small bowel capsule endoscopy (SBCE) and device-assisted enteroscopy are the main endoscopic techniques for the study of the small bowel, the latter additionally providing sampling and therapeutic options, and hence acting complementary to SBCE in the diagnostic work-up. Although a single diagnostic modality is often insufficient in the setting of SBTs, SBCE is a fundamental tool to drive further management towards a definitive diagnosis. The aim of this paper is to provide a concise narrative review of the role of SBCE in the diagnosis and management of SBTs.

Can High-Frequency Intraoral Ultrasound Predict Histological Risk Factors in Oral Squamous Cell Carcinoma? A Preliminary Experience.

Despite advancements in multidisciplinary care, oncologic outcomes of oral cavity squamous cell carcinoma (OSCC) have not substantially improved: still, one-third of patients affected by stage I and II can develop locoregional recurrences. Imaging plays a pivotal role in preoperative staging of OSCC, providing depth of invasion (DOI) measurements. However, locoregional recurrences have a strong association with adverse histopathological factors not included in the staging system, and any imaging features linked to them have been lacking. In this study, the possibility to predict histological risk factors in OSCC with high-frequency intraoral ultrasonography (IOUS) was evaluated. Thirty-four patients were enrolled. The agreement between ultrasonographic and pathological DOI was evaluated, and ultrasonographic margins' appearance was compared to the Brandwein-Gensler score and the worst pattern of invasion (WPOI). Excellent agreement between ultrasonographic and pathological DOI was found (mean difference: 0.2 mm). A significant relationship was found between ultrasonographic morphology of the front of infiltration and both Brandwein-Gensler score ≥ 3 (p < 0.0001) and WPOI ≥4 (p = 0.0001). Sensitivity, specificity, positive predictive value, and negative predictive value for the IOUS to predict a Brandwein-Gensler score ≥3 were 93.33%, 89.47%, 87.50%, and 94.44%, respectively. The present study demonstrated the promising role of IOUS in aiding risk stratification for OSCC patients.

Gastrointestinal Tract Cancers, an Increasing Burden of the Modern Era: Epidemiology and Prevention.

Gastrointestinal tract cancers, including oral, oesophageal, stomach, liver, pancreas, and colorectal cancers, represent a significant worldwide health concern [...].

Real-world efficacy and safety of vedolizumab in managing ulcerative colitis versus Crohn's disease: results from an Italian multicenter study.

BACKGROUND: Vedolizumab (VDZ) can be used to treat refractory ulcerative colitis (UC) and Crohn's disease (CD). We assessed whether there are differences in treating UC vs CD with VDZ. RESEARCH DESIGN AND METHODS: Mayo score in UC and the Harvey-Bradshaw Index (HBI) in CD scored the clinical activity. Achievement and maintenance of clinical remission during the follow-up, and safety were the primary endpoints. RESULTS: 729 patients (475 with UC and 254 with CD), median follow-up of 18 (IQR 6-36) months, were enrolled. Clinical remission at the 6th month of treatment was achieved in 488 (66.9%) patients (74.4% in CD vs 62.9% in UC, p<0.002) while, during the follow-up, no difference was found (81.5% in the UC group and 81.5% pts in the CD group; p=0.537). The clinical remission at the 6th month of treatment (p=0.001) and being naïve to biologics (p<0.0001) were significantly associated with prolonged clinical remission. The clinical response was significantly higher in UC (90.1%) vs CD (84.3%) (p=0.023), and surgery occurred more frequently in CD (1.9% in UC vs 5.1% in CD, p=0.016). CONCLUSION: We found differences when using VDZ in UC vs CD in real life. These parameters can help the physician predict this drug's longterm efficacy.

Immune checkpoint inhibitors in malignancies after liver transplantation: A systematic review and pooled analysis.

BACKGROUND AND AIMS: Treatment of de novo malignancies and recurrent hepatocellular carcinoma with immune checkpoint inhibitors (ICI) in liver transplant recipients (LT) is an attractive strategy that is infrequently pursued because of the lack of strong evidence regarding their safety and efficacy. In this systematic review with pooled analysis, we aimed to assess safety and efficacy of ICI therapy following LT. METHODS: We performed a systematic search of case reports and series published until January 2022. We included 31 publications reporting a total of 52 patients treated with ICIs after LT and assessed in a pooled analysis the risk of graft rejection and the outcome of ICI therapy. RESULTS: Acute graft rejection occurred in 15 patients (28.8%) and 7 patients (13.4% of the total cohort) died because of graft loss. Rejection was associated with shorter overall survival (OS) (17.2 months, confidence interval [CI] 12.1-22.2 vs. 3.5 months, CI 1.6-5.4, p < 0.001). Disease control rate was 44.2% (n = 23), and in these patients, OS was longer than in non-responders (26.4 months, CI 20.8-32.0 vs. 3.4 months, CI 2.1-4.7, p < 0.001). CONCLUSIONS: Observational, off-label experience suggests that treatment with ICI for advanced malignancies in LT recipients might not be discarded a priori. This notwithstanding, ICI treatment in these patients is associated with a substantial risk of graft rejection and mortality. Prospective studies are needed to provide adequate safety and efficacy figures of ICI treatment in this fragile population.

Colorectal Cancer in Inflammatory Bowel Diseases: Epidemiology and Prevention: A Review.

Colorectal cancer (CRC) is currently the third most frequent form of malignancy and the second in terms of mortality. Inflammatory bowel diseases (IBDs) are recognized risk factors for this type of cancer. Despite a worldwide increase in the incidence of CRC, the risk of CRC-related death in IBD patients has declined over time, probably because of successful surveillance strategies, the use of more effective drugs in the management of remission and improved indications to colectomy. This notwithstanding, CRC 5-year survival in patients with IBD is poorer than in the general population. This review provides a summary of the epidemiological features, risk factors and various prevention strategies proposed for CRC in IBD patients. Moreover, there is a special focus on reporting and highlighting the various prevention strategies proposed by the most important international scientific societies, both in terms of chemoprevention and endoscopic surveillance. Indeed, in conducting the analysis, we have given attention to the current primary, secondary and tertiary prevention guidelines, attempting to emphasize unresolved research and clinical problems related to this topic in order to improve diagnostic strategies and management.

Effect of contrast-enhanced ultrasound (CEUS) on liver stiffness measurements obtained by transient and shear-wave elastography.

BACKGROUND: Since liver fibrosis is one of the most accurate predictors of prognosis in hepatopatic patients, its accurate assessment and staging is a major public health issue. Transient elastography (TE) (Fibroscan, Echosens, Paris, France) and shear wave elastography (SWE) represent the gold standard techniques among non-invasive methods to assess liver fibrosis. Contrast-enhanced ultrasound (CEUS) is increasingly used to diagnose the nature of liver lesions and is often performed together with TE and SWE. In this study we evaluated the effect of CEUS on liver stiffness measurements obtained by TE and SWE. METHODS: A retrospective analysis of ultrasound (US) exams performed by an expert operator was carried out. TE and SWE were performed 30 seconds before and after the execution of CEUS. Statistical analysis was carried out using the statistical software R. Kolmogorov-Smirnov analysis was performed to test the normality of continuous variables. The pre- and post-CEUS liver stiffness values were compared using the Wilcoxon's Test. RESULTS: Ninety-six patients were enrolled. While the measurements were comparable when performed with TE, those obtained by SWE decreased by 6% after administration of the contrast agent (P=0.0005). Fibrosis stage deviated between pre- and post-CEUS in 16 (17%) patients with Fibroscan and 22 (23%) patients with SWE. Among the latter, in 9 cases (10%) a deviation from absent-low (F0-F2) to high-fibrosis (F3, F4), or vice versa, occurred. CONCLUSIONS: Our study, the first to assess the effects of CEUS on US elastography, shows that the contrast agent (Sonovue, Bracco Suisse SA, Cadempino, Switzerland) does not significantly affect liver stiffness measurements obtained by TE, whereas the accuracy decreases when performed by SWE.

Pediatric gastroenteropancreatic neuroendocrine tumor: A case report and review of the literature.

INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of epithelial neoplasms originating from the diffuse neuroendocrine cell system of the gastrointestinal tract and pancreas. They are very rare, especially in pediatric age, and vary widely in terms of clinical presentation, malignant potential, and prognosis. PATIENT CONCERNS: A 9 years' old, white female child presented with abdominal pain and diarrhea mixed with bright red blood lasting 2 days followed by hematemesis. DIAGNOSIS: Routine laboratory tests revealed microcytic anemia. Upper endoscopy showed a 20-mm polypoid lesion in the posterior wall of the duodenal bulb. Biopsy specimens were taken and histologic analysis showed a well-differentiated neuroendocrine tumor G1, with a ki-67 index <2%, an expression of chromogranine A (CgA), synaptophysin and somatostatin receptor type 2A (SSTR2A). Endoscopic ultrasound showed a 21-mm hypoechoic, hypervascular lesion involving the mucosal, submucosal, and muscular layers and a 15-mm hypoechoic round periduodenal lymph node. Gallium-68-somatostatin receptor positron emission tomography (PET with Ga-DOTATOC) showed one area of tracer uptake in the duodenum and other one near the duodenum compatible with the primary tumor site and a lymph node respectively. All the tests confirmed the diagnosis of a GEP-NET of the duodenal bulb, with a single lymph-node metastasis. INTERVENTIONS: The patient underwent an open duodenal wedge resection. OUTCOMES: The follow-up at 6, 24, and 36 months and then yearly after surgery for a total of 42 months showed no evidence of recurrence. CONCLUSION: Duodenal neuroendocrine tumors represent 1% to 3% of all GEP-NETs. They are rare in adults and extremely rare in children. Therefore, the diagnostic and therapeutic approach should be multidisciplinary, including laboratory, endoscopic, and specific imaging tests and strictly follows guidelines, to avoid misdiagnosis and inadequate treatments. Although the prognosis is benign in most cases, they can present with metastases. Therefore, a careful follow-up is extremely important.

Growth changes after gluteen free diet in pediatric celiac patients: a literature-review.

BACKGROUND: Celiac disease is an auto-immune disorder characterized by clinical manifestations that appear in genetically predisposed subjects after gluten ingestion. In the last years, there has been a progressive change in clinical manifestations. Our aim was to evaluate the nutritional status of children with celiac disease at diagnosis and how the gluten-free diet (GFD) influences their growth. METHODS: A search on PubMed/Medline was performed using "celiac disease", "body mass index" and "children" as key words.  Medline, Scopus, PubMed publisher and Google Scholar were searched as well.  We selected clinical studies describing the nutritional status of patients before and after GFD using indicators like height, weight, BMI, skeletal age.  We excluded papers referred to adult population or in which other diseases were related to celiac disease. Also literature-reviews were excluded. RESULTS: From 1999 to 2018, 10 studies were found. Overall, 1383 patients in pediatric age were evaluated for their nutritional status at diagnosis of celiac disease and after a variable period from 1 to 17 years of GFD. Indicators considered were height, weight, BMI and skeletal age. CONCLUSIONS: the nutritional status of celiac patients at diagnosis is variable including an increasing number of overweight and obese. GFD has a beneficial impact on growth changes determining a correction of BMI distribution towards a Gaussian shape.

Thyroid and celiac disease in pediatric age: a literature review.

Chronic autoimmune thyroid disease or Hashimoto thyroiditis (HT) and Graves-Basedow disease (GD) are the main autoimmune thyroid diseases in pediatric age. Both are characterized by the production of anti-thyroid antibodies, by an infiltration of autoreactive B and T lymphocytes into the thyroid parenchyma and by alterations in thyroid function (hyperthyroidism in GD, normal function or subclinical hypothyroidism in HT with possible evolution towards manifest hypothyroidism). Celiac disease (CD) is a systemic autoimmune disease caused by gluten ingestion in genetically predisposed subjects, its prevalence is around 1% in Western Countries. It presents with a pathognomonic enteropathy, a variety of clinical manifestations, positivity for specific antibodies, positivity for typical haplotypes HLA DQ2/DQ8. The clinical manifestations may vary among four types: typical, atypical, silent and latent. Diagnosis can be made in presence of specific histopathologic findings in duodenal biopsies and antibodies positivity. Celiac disease is associated to various endocrine autoimmunities such as thyropathies, diabetes mellitus type 1, Addison disease, multiendocrine syndromes. The most frequent associated thyropaties are HT and GD. The present review aims to explore the associations between thyropathies and celiac disease in pediatric age.

Endoscopic ultrasound in pediatric population: a comprehensive review of the literature.

BACKGROUND AND AIM: Endoscopic ultrasonography (EUS) with or without fine needle aspiration/biopsy (FNA/B) is a well-established diagnostic tool in adults for the evaluation and management of gastrointestinal (GI) tract disorders. Its use in children is still limited as well as literature in pediatric age is limited, although the application of EUS is now increasing. The present article aims to review the current literature about EUS indication, accuracy and safety in pediatric age. METHODS: Electronic literature searches were conducted using Pubmed, Medline, Embase, and the Cochrane Central Register of Controlled Trials using the word pediatric endoscopic ultrasound, pediatric pancreaticobiliary AND/OR EUS, pediatric EUS technique. Main patients and procedures characteristics were analyzed. The primary endpoint was the indication of EUS. Secondary endpoints were the accuracy of the technique and the incidence of complications. RESULTS: Data were extracted from 19 articles. A total of 571 patients were investigated, with a median age of 12,7 years. A total of 634 EUS procedures were performed. The majority of EUS procedures investigated the pancreaticobiliary tract (77,7%). Most studies showed a high positive impact on management with a median value of 81,7%. No major complications were reported. Five studies reported minor complications with a median value of 2%. CONCLUSIONS: EUS is safe and has a significant role in the diagnosis of pancreaticobiliary and GI diseases even in children, with a high therapeutic success. An increasing EUS utilization by pediatric gastroenterologists is expected and offering dedicated EUS training to some selected pediatric gastroenterologists might be indicated.

Applications of wireless capsule endoscopy in pediatric age: an update.

BACKGROUND: The small bowel has often been considered the mysterious "black hole" of the gastrointestinal tract. With regards to this, the development of the wireless capsule endoscopy (WCE) has represented a turning point. It is a non-invasive technique, enabling an excellent visualization of the small bowel (SB) mucosa without the use of radiation. The WCE was approved by the Food and Drug Administration (FDA) in 2001 for adults and in 2004 for children. The aim of the present review is to provide an update on indications, diagnostic yield, safety and limitations of WCE in children. Even though literature regarding the use of WCE in pediatric age is more limited than in adults, WCE is a useful and safe diagnostic tool for the exploration of the small bowel also in children. The indications for WCE are similar at any age, however the main indication in children is Crohn's disease (CD), while in the adults is the research of SB bleeding. The main limitation in pediatric age is the possibility for younger children to swallow the capsule. WCE in pediatric is a rapidly advancing technology and has the potential to further transform the evaluation and management of SB disease.

Inverse association between Helicobacter pylori and inflammatory bowel disease: myth or fact?

BACKGROUND: Inflammatory bowel diseases (IBD), are chronic, relapsing-remitting diseases of the gastrointestinal tract, including Crohn's disease (CD), Ulcerative colitis (UC) and Unclassified IBD (IBDU). Their pathogenesis involves genes and environment as cofactors in inducing autoimmunity; particularly the interactions between enteric pathogens and immunity is being studied. Helicobacter pylori (HP) is common pathogen causing gastric inflammation. Studies found an inverse prevalence association between HP and IBD, suggesting a potential protecting role of HP from IBD. METHODS: A literature search of the PubMed database was performed using the key words ''helicobacter pylori'', ''inflammatory bowel disease'', ''crohn disease'', "ulcerative colitis". Embase, Medline (OvidSP), Web of Science, Scopus, PubMed publisher, Cochrane and Google Scholar were also searched. Prevalence rate-ratios among HP in IBD patients, HP in CD patients, HP in UC patients, HP in IBDU patients were extracted, each group was compared with controls, to verify the inverse association between HP and IBD prevalence. RESULTS: In all groups the dispersion of data suggested an inverse association between IBD group and controls, even when the comparison was carried out separately between each group of newly diagnosed patients and controls, to rule out the possible bias of ongoing pharmacologic therapy. CONCLUSIONS: The results of this review show a striking inverse association between HP infection and the prevalence of IBD, independently from the type of IBD considered across distinct geographic regions. Anyway, data should be interpreted cautiously, as wider, prospective and more homogeneous research on this topic are awaited, which could open new scenarios about environmental etiology of IBD.

Hemolytic uremic syndrome: differential diagnosis with the onset of inflammatory bowel diseases.

BACKGROUND: Shiga-toxin Escherichia coli productor (STEC) provokes frequently an important intestinal damage that may be considered in differential diagnosis with the onset of Inflammatory Bowel Disease (IBD). The aim of this work is to review in the current literature about Hemolytic Uremic Syndrome (HUS) and IBD symptoms at the onset, comparing the clinical presentation and symptoms, as the timing of diagnosis and of the correct treatment of both these conditions is a fundamental prognostic factor. A focus is made about the association between typical or atypical HUS and IBD and a possible renal involvement in patient with IBD (IgA-nephropathy). METHODS: A systematic review of scientific articles was performed consulting the databases PubMed, Medline, Google Scholar, and consulting most recent textbooks of Pediatric Nephrology. RESULTS: In STEC-associated HUS, that accounts for 90% of cases of HUS in children, the microangiopathic manifestations are usually preceded by gastrointestinal symptoms. Initial presentation may be considered in differential diagnosis with IBD onset. The transverse and ascending colon are the segments most commonly affected, but any area from the esophagus to the perianal area can be involved. The more serious manifestations include severe hemorrhagic colitis, bowel necrosis and perforation, rectal prolapse, peritonitis and intussusception. Severe gastrointestinal involvement may result in life-threatening complications as toxic megacolon and transmural necrosis of the colon with perforation, as in Ulcerative Colitis (UC). Transmural necrosis of the colon may lead to subsequent colonic stricture, as in Crohn Disease (CD). Perianal lesions and strictures are described. In some studies, intestinal biopsies were performed to exclude IBD. Elevation of pancreatic enzymes is common. Liver damage and cholecystitis are other described complications. There is no specific form of therapy for STEC HUS, but appropriate fluid and electrolyte management (better hyperhydration when possible), avoiding antidiarrheal drugs, and possibly avoiding antibiotic therapy, are recommended as the best practice. In atypical HUS (aHUS) gastrointestinal manifestation are rare, but recently a study evidenced that gastrointestinal complications are common in aHUS in presence of factor-H autoantibodies. Some report of patients with IBD and contemporary atypical-HUS were found, both for CD and UC. The authors conclude that deregulation of the alternative complement pathway may manifest in other organs besides the kidney. Finally, searching for STEC-infection, or broadly for Escherichia coli (E. coli) infection, and IBD onset, some reviews suggest a possible role of adherent invasive E. coli (AIEC) on the pathogenesis of IBD. CONCLUSIONS: The current literature shows that gastrointestinal complications of HUS are quite exclusive of STEC-associated HUS, whereas aHUS have usually mild or absent intestinal involvement. Severe presentation as toxic megacolon, perforation, ulcerative colitis, peritonitis is similar to IBD at the onset. Moreover, some types of E. coli (AIEC) have been considered a risk factor for IBD. Recent literature on aHUS shows that intestinal complications are more common than described before, particularly for patients with anti-H factor antibodies. Moreover, we found some report of patient with both aHUS and IBD, who benefit from anti-C5 antibodies injection (Eculizumab).

Clinical approach to the patient with acute gastrointestinal bleeding.

Gastrointestinal bleeding (GIB) is a very common condition at all ages, with high rates of morbidity and mortality, especially in case of acute presentation. The optimal management of acute GIB requires a timely overview of vital signs and clinical presentation to stabilize the patient if necessary and set up the most adequate diagnostic and therapeutic approach, based on the suspected etiology. Endoscopy plays a major role both in diagnosis and treatment of acute GIB, as allows the application of several hemostasis techniques during the diagnostic session, which should preferably be performed within 24 hours from the acute event. The hemostasis technique should be chosen based on type, etiology of the bleeding and the operator preference and expertise. Nevertheless, several challenging cases need the cooperation of radiology especially in the diagnostic phase, and even in the therapeutic phase for those bleedings in which medical and endoscopic techniques have failed. Imaging diagnostic techniques include mainly CT angiography, scintigraphy with labeled erythrocytes and arteriography. This last technique plays also a therapeutic role in case arterial embolization is needed. Only those patients in which the previous techniques have failed, both in diagnosis and treatment, are candidates for emergency surgery.

Non-invasive tests for the diagnosis of helicobacter pylori: state of the art.

Usually, non-invasive tests are the first methods for diagnosing Helicobacter pylori (HP) infection. Among these, serological test, stool antigen research and urea breath test are the most used. Antibodies anti-HP are not recommended in low prevalence population, moreover they cannot reveal an ongoing infection, but they only prove a contact with the bacterium. Also, they can persist for a long time after the eradication of the infection, therefore, they should not be used to verify the success of eradication therapy. Stool antigen research and Urea Breath Test (UBT) are useful both in diagnosis and during follow-up after eradication treatment. The stool antigen test is cheaper than Urea breath test with similar sensitivity and specificity.  Non-invasive tests are not able to diagnose the associated complications to HP infection.

How and when investigating and treating Helicobacter pylori infection in children.

For thousands of years humans have lived in symbiosis with Helicobacter pylori. This infection is acquired mainly during childhood and, despite it represents one of the most common infections in humans, only a minority of infected people may develop health issues and life-threatening diseases. For diagnosing Helicobacter pylori infection in children we can use, at first, non-invasive diagnostic tests, if clinical pattern and/or history are of suspicion. Then, invasive tests i.e. gastroscopy are necessary to confirm the infection. As antibiotics are not widely available in children affected by Helicobacter pylori infection, they should be chosen based on individual antibiotic susceptibility testing obtained by gastric biopsy specimens or the local antibiotic resistance pattern, in empirical treatment is chosen. Test and treat strategy in children should be avoided. In this brief review we summarize how and in which children the infection should be investigate and which the most appropriate eradication treatment should be chosen.