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Background and aims Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients’ management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. Methods Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008–2017 who underwent a genetic workup were collected. Results Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. Conclusion A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients’ management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.

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Primary immunodeficiency (PID) with immune dysregulation may present with early onset gastrointestinal autoimmune disorders. When gastrointestinal autoimmunity is associated with multiple extraintestinal immune system dysfunction the diagnosis of PID is straightforward. However, with the advent of next generation sequencing technologies, genetic defects in PID genes have been increasingly recognized even when a single or no extraintestinal signs of immune dysregulation are present. A genetic diagnosis is especially important considering the expanding armamentarium of therapies designed to inhibit specific molecular pathways. We describe a boy with early-onset severe, refractory autoimmune gastritis and biallelic mutations in the LRBA gene causing a premature STOP-codon who was successfully treated with CTLA4-Ig, abatacept, with long term clinical and endoscopic remission. The case underscores the importance to consider a monogenetic defect in early onset autoimmune disorders, since the availability of targeted treatments may significantly improve patient prognosis.

Carcinoma of the ampulla of Vater is an uncommon neoplasm and represents 0.5% of all gastrointestinal malignancies, being less common than carcinoma of the pancreas and bile ducts. The most common ampullary tumor is the adenocarcinoma with tubular growth pattern. Signet ring cell carcinoma is extremely rare. In this article, we report a case of signet ring cell carcinoma of the ampulla of Vater showing focal neuroendocrine amphicrine differentiation and intestinal phenotype, which occurred in a 49-year-old male who is still alive 7 years after surgery, without evidence of recurrence. This long-term survival might be attributed not only to the early stage of the disease but also to the neuroendocrine differentiation and the absence of genetic alterations.

Background: The recurrence rate, related to the unpredictable behavior of gastrointestinal stromal tumors (GISTs), continues to be a major topic of investigation, since no actual risk evaluation scales have proven to be exceedingly effective in predicting prognosis. We therefore focus in this study on investigating the predictive variables of disease recurrence. Methods: Between September 2004 and January 2011, 34 patients, 18 males and 16 females with a median age of 62 (range, 27-87) years, underwent operations for primary, localized and advanced GISTs. Immunohistochemical profile, KIT and the platelet-derived growth factor receptor-alpha (PDGFR-α) gene mutations, tumor size, tumor site, mitotic index, synchronous tumors, adjuvant therapy, symptoms and gender were considered and analyzed as predictive variables. The receiver operating characteristic (ROC) analysis was used to determine the optimal cut-off value for tumor dimension to predict recurrence. Results: The median follow-up (FU) was 20 months (range, 6-86 months). A first-line adjuvant therapy was performed in nine patients. Disease relapse occurred in five cases. The tumor size and the mitotic index were the strongest predictive factors (P

Background: Dermatitis Herpetiformis (DH) diagnosis relies on direct immunofluorescence (DIF) on skin biopsy. Serology for anti-epidermal transglutaminase antibodies (Anti-TG3 Abs) has attracted interest, being inexpensive and less invasive. However, the available test has variable sensitivity and low specificity in Coeliac Disease (CD) patients without DH. Objective: To evaluate the diagnostic accuracy and reproducibility of a novel quantitative ELISA for the measurement of Anti-TG3 Abs. Methods: ELISA was set-up with recombinant TG3 and a standard curve based on a human recombinant monoclonal IgA anti-TG3. Sera of 57 DH patients, 212 CD patients, 120 patients with non-gluten related gastrointestinal diseases (CTRL) and 168 healthy controls (HC) were tested. Results: The test was reproducible with high sensitivity (91%). Test specificity was high when considering HC (99%) as well as CTRL (98%). Interestingly in CD patients test specificity was agedependent and was higher (97%) in patients ≤ 25 years of age. Limitations: Not all DH were confirmed by DIF. Conclusion: The ELISA test could be used as a screening tool when DH is clinically suspected and may serve as a sole diagnostic test in younger patients. The quantification of Anti-TG3 Abs levels will facilitate the comparison of results from different laboratories.

Background No study has compared the performance of light microscopy (LM) and whole slide imaging (WSI) for endoscopic ultrasound (EUS) histological acquired tissue samples from pancreatic solid lesions (PSLs). We evaluated the concordance between LM and WSI and the inter- and intra-observer agreements among pathologists on PSLs EUS acquired samples. Methods LM and WSI from 60 patients with PSLs were evaluated by five expert pathologists to define: diagnostic classification, presence of a core, number and percentage of lesional cells. Washout period between evaluations was 3 months. Time of the procedures was also assessed. Results Forty-eight cell-block and 12 biopsy samples were evaluated. A high concordance between LM and WSI was found. Inter- and intra-observer agreements for diagnostic classification were substantial and complete, respectively. For all the other parameters, the inter-observer agreement was usually higher for LM. For the intra-observer, a substantial agreement was reached regarding the presence of tissue core and the number and the percentage of malignant cells. Median time for performing LM was significantly shorter than for WSI (p Conclusions LM and WSI of cell-block and biopsy samples acquired by EUS in PSLs were highly concordant, with a substantial inter-observer and a complete intra-observer agreements regarding diagnostic classification.

Background: as the paradigm for IBD management is evolving from symptom control to the more ambitious goal of complete deep remission, the concept of personalized medicine, as a mean to deliver individualized treatment with the best effectiveness and safety profile, is becoming paramount. Therapeutic drug monitoring (TDM) is an essential part of personalized medicine and its role in the management of IBD patients is rapidly expanding. Objective: to review the current knowledge that poses the rationale for the use of TDM, and the present and future role of TDM-based approaches in the management of pediatric IBD. Method: literature review. Results: the concept of TDM has been introduced in the field of IBD along with thiopurines, over a decade ago, and evolved around anti-TNF therapies. TDM-based strategies proved to be costeffective in the management of patients with loss of response to biologics and, more recently, proactive TDM to optimize drug exposure has been shown to reduce treatment failure and drug adverse events. The role of TDM with new biologics and the usefulness of software-systems support tools to guide drug dosing are now under investigation. Conclusion: Therapeutic drug monitoring has the potential to maximize the cost-benefit profile of therapies and is becoming an essential part of IBD management.

Background Congenital cytomegalovirus (CMV) infection is a major cause of central nervous system damage leading to sensorineural hearing loss, mental retardation and cerebral palsy. Objectives Identify the type of organ involvement and understand the histopathogenesis of damage in foetuses of women with a CMV-highly positive amniotic fluid. Study design 34 foetuses with congenital CMV infection documented by prenatal diagnosis were studied. Three foetuses died in utero . The remaining pregnancies were electively terminated at 20–21 weeks gestation. Results Foetal organs positive for CMV antigens were: placenta (100%), pancreas (100%), lung (87%), kidney (87%), liver (71%), brain (55%) and heart (44%). Inflammatory infiltrate was almost always present in CMV-infected foetal organs and the severity of the inflammatory response was correlated with the organ damage. Brain damage with necrosis was observed in 33% (9/27) and a mild telencephalic leukoencephalopathy in 22% (6/27) of foetuses studied. Conclusions Focal necrosis was observed very frequently in organs such as pancreases, livers, hearts and kidneys. However the damage in these organs is likely to be resolved by parenchymal regeneration. Brain damage, which seems to be the results of a combined effect of viral infection, inflammatory infiltration and hypoxia due to severe placentitis, is less likely to be resolved because of the low regeneration ability of this organ.

Intraductal papillary mucinous neoplasms are a well-recognized pathologic entity of the pancreas that is being reported with increasing frequency. These tumours carry a relatively favourable prognosis and are frequently associated with extrapancreatic malignancies. The combination of advanced age and co-existence of two neoplasms challenges the planning of the best treatment option. A 78-year-old man presented with rectal bleeding which led to the diagnosis of a stenosing adenocarcinoma of the sigmoid colon. No metastatic lesions were present but a 30 mm intraductal papillary mucinous neoplasm with mural nodules was detected in the uncinate process of the pancreas. Small diffused dilations of the side branches were present in the body and tail of the gland. A two-stage procedure was planned: an R0 sigmoid resection was undertaken first with an uneventful postoperative course. Forty-five days later a pancreaticoduodenectomy was performed and the postoperative course was again uneventful apart from delayed gastric emptying. Histology showed a combined-type intraductal papillary mucinous neoplasm with foci of non-invasive carcinoma. The patient is still alive without evidence of cancer recurrence 33 month after the pancreatico-duodenectomy. The co-existence of a potentially malignant pancreatic tumour with an extra-pancreatic overt malignancy in elderly patients poses difficulties in the attempt to cure the patient with minimal morbidity. In the present case we considered a staged surgical procedure with the aim of reducing the perioperative risk, since the excision of the pancreatic neoplasm required a pancreaticoduodenectomy in an elderly patient.