Viscoelastic properties of small bowel mesentery at MR elastography in Crohn's disease: a prospective cross-sectional exploratory study.

BACKGROUND: Creeping fat is a pathological feature of small bowel Crohn's disease (CD), with literature suggesting that bowel resection with extended mesenteric resection is related to less postoperative recurrences. Conventional imaging is unable to accurately quantify the disease involvement (i.e., fibrosis) of creeping fat. Quantification of disease involvement could be useful in decision-making for additional extended mesenteric resection. We investigated the feasibility of magnetic resonance elastography (MRE) of the mesentery and if MRE is capable to detect fibrotic disease involvement of mesentery in active CD. METHODS: Multifrequency MRE yielded spatial stiffness (shear wave speed, SWS, |G*|) and fluidity maps (φ). Viscoelastic properties of seven CD patients' mesentery were compared to age- and sex-matched healthy volunteers (HV) (Mann-Whitney U-test). Within CD patients, the affected and "presumably" unaffected mesentery were compared (Wilcoxon-signed rank test). Repeatability was tested in 15 HVs (Bland-Altman analysis, coefficient of variation [CoV]). Spearman rank correlations were used to investigate the relation between microscopically scored amount of mesenteric fibrosis and viscoelastic parameters. RESULTS: SWS, |G*|, and φ of affected mesentery in CD were higher compared to HV (p = 0.017, p = 0.001, p = 0.017). Strong correlations were found between percentage of area of mesenteric fibrosis and SWS and |G*| (p < 0.010). No differences were found within CD between affected and presumably unaffected mesentery. Repeatability of SWS showed 95% limits of agreement of (-0.09, 0.13 m/s) and within-subject CoV of 5.3%. CONCLUSION: MRE may have the potential to measure fibrotic disease involvement of the mesentery in CD, possibly guiding clinical decision-making with respect to extended mesenteric resection. TRIAL REGISTRATION: Dutch trial register, NL9105 , registered 7 December 2020. RELEVANCE STATEMENT: MRE may have the potential to measure the amount of mesenteric fibrosis of the affected mesenteric fat in active Crohn's disease, giving more insight into disease progression and could potentially play a role in clinical decision-making for extended mesenteric resection. KEY POINTS: • MRE of the mesentery in patients with active CD is feasible. • Fluidity and stiffness of the mesentery increase in active CD, while stiffness correlates with the histopathological amount of mesenteric fibrosis. • MRE provides biomarkers to quantify mesenteric disease activity in active CD.

Adult-Onset Autoimmune Enteropathy in an European Tertiary Referral Center.

INTRODUCTION: Adult-onset autoimmune enteropathy (AIE) is a rare cause of severe chronic diarrhea because of small intestinal villous atrophy. We report on patients with adult-onset AIE in an European referral center. METHODS: Retrospective study including patients diagnosed with AIE in the Amsterdam UMC, location VUmc, between January 2003 and December 2019. Clinical, serological, and histological features and response to treatment were reported. The specificity of antienterocyte antibodies (AEA) was evaluated by examining the prevalence of AEA in (i) controls (n = 30) and in patients with (ii) AIE (n = 13), (iii) celiac disease (CD, n = 52), (iv) refractory celiac disease type 2 (n = 18), and (v) enteropathy-associated T-cell lymphoma (EATL, n = 10). RESULTS: Thirteen AIE patients were included, 8 women (62%), median age of 52 years (range 23-73), and 6 (46%) with an autoimmune disease. AEA were observed in 11 cases (85%), but were also found in CD (7.7%), refractory celiac disease type 2 (16.7%), and EATL (20%). Ten patients (77%) were human leukocyte antigen DQ2.5 heterozygous. Total parenteral nutrition was required in 8 cases (62%). Steroids induced clinical remission in 8 cases (62%). Step-up therapy with rituximab, cyclosporine, infliximab, and cladribine in steroid-refractory patients was only moderately effective. Four patients died (31%), but 4 (31%) others are in long-term drug-free remission after receiving immunosuppressive treatment, including 1 patient who underwent autologous stem cell transplantation. DISCUSSION: Adult-onset AIE is a rare but severe enteropathy that occurs in patients susceptible for autoimmune disease. Four patients (31%) died secondary to therapy-refractory malabsorption, while immunosuppressive therapy leads to a long-lasting drug-free remission in one-third of patients.

Immune-mediated enteropathies: From bench to bedside.

Immune-mediated enteropathies are caused by excessive reactions of the intestinal immune system towards non-pathogenic molecules. Enteropathy leads to malabsorption-related symptoms and include (severe) chronic diarrhea, weight loss and vitamin deficiencies. Parenteral feeding and immunosuppressive therapy are needed in severe cases. Celiac disease has long been recognized as the most common immune-mediated enteropathy in adults, but the spectrum of immune-mediated enteropathies has been expanding. Histological and clinical features are sometimes shared among these enteropathies, and therefore it may be challenging to differentiate between them. Here, we provide an overview of immune-mediated enteropathies focused on clinical presentation, establishing diagnosis, immunopathogenesis, and treatment options.

Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy. METHODS: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course. FINDINGS: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41-78). Median disease course (time from onset of symptoms to death) was 22 days (range 5-44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5-44]; ten patients with neutrophilic plugs, 21 days [5-44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets.. INTERPRETATION: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19. FUNDING: Amsterdam UMC Corona Research Fund.

Vulvar and vaginal neoplasia in women with inflammatory bowel disease.

Immunosuppressive drugs are the cornerstone in the treatment of inflammatory bowel disease (IBD), however they are associated with an increased risk of extra-intestinal cancer. Whether the risk for female genital tract malignancies, including vulvar and vaginal cancer, is increased is less clear. Our aim was to investigate the risk of these malignancies in IBD-patients. Histopathological data of all IBD patients with a vulvar or vaginal (pre-)cancerous lesion were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology from 1991 to 2015. Medical history was retrieved from patient records. Data from the Central Office for Statistics, the Dutch comprehensive cancer organization, and the IBDSL cohort were obtained to calculate the standardized, and age-adjusted incidence rates. Fifty-five patients met the inclusion criteria. A standardized incidence rate of 1.2(95% CI:0.8-1.7) for vulvar and vaginal carcinoma among adult female IBD was calculated, which did not significantly differ from the general population. The use of immunosuppressive therapy did not increase the occurrence of vulvovaginal malignancy, nor did it influence the recurrence rate. However, immunosuppressive drugs ever-users were on average 11 years younger at the time of their gynaecological diagnosis. Overall, our data do not support intensified screening for vulvar or vaginal malignancies in female IBD patients.

Increased colon cancer risk after severe Salmonella infection.

BACKGROUND: Colon cancer constitutes one of the most frequent malignancies. Previous studies showed that Salmonella manipulates host cell signaling pathways and that Salmonella Typhimurium infection facilitates colon cancer development in genetically predisposed mice. This epidemiological study examined whether severe Salmonella infection, usually acquired from contaminated food, is associated with increased colon cancer risk in humans. METHODS AND FINDINGS: We performed a nationwide registry-based study to assess colon cancer risk after diagnosed Salmonella infection. National infectious disease surveillance records (1999-2015) for Dutch residents aged ≥20 years when diagnosed with salmonellosis (n = 14,264) were linked to the Netherlands Cancer Registry. Salmonella-infected patients were laboratory-confirmed under medical consultation after 1-2 weeks of illness. These datasets also contained information on Salmonella serovar and type of infection. Colon cancer risk (overall and per colon subsite) among patients with a diagnosed Salmonella infection was compared with expected colon cancer risk in the general population. Data from the nationwide registry of histo- and cytopathology (PALGA) and Statistics Netherlands (CBS) allowed assessing potential effects of age, gender, latency, socioeconomic status, genetic predisposition, inflammatory bowel disease (IBD), and tumor features. We found that compared to the general population, colon cancer risk was significantly increased (standardized incidence ratio [SIR] 1.54; 95%CI 1.09-2.10) among patients with Salmonella infection diagnosed <60 years of age. Such increased risk concerned specifically the ascending/transverse colon (SIR 2.12; 95%CI 1.38-3.09) after S. Enteritidis infection (SIR 2.97; 95%CI 1.73-4.76). Salmonellosis occurred more frequently among colon cancer patients with pre-infectious IBD, a known risk factor for colon cancer. Colon tumors of patients with a history of Salmonella infection were mostly of low grade. CONCLUSIONS: Patients diagnosed with severe salmonellosis have an increased risk of developing cancer in the ascending/transverse parts of the colon. This risk concerns particularly S. Enteritidis infection, suggesting a contribution of this major foodborne pathogen to colon cancer development.

The first cases of collagenous sprue successfully treated with thioguanine.

OBJECTIVE: Collagenous sprue (CS) is a rare form of small bowel enteropathy characterised by a thickened basement membrane and is, in most of the literature, reported as part of coeliac disease. Multiple treatment strategies are suggested in CS, but there is no standardised therapy. The aim of this series is to describe 4 cases of CS and to propose thioguanine (6-TG) treatment. DESIGN: We reviewed 4 cases of CS. Data were obtained from our prospective database of patients referred to our coeliac centre. Evaluation of small bowel biopsies was performed by an expert pathologist. RESULTS: None of the patients had ever had coeliac-specific antibodies, and all were negative for HLA-DQ2 and HLA-DQ8 phenotype. Three patients were treated with a combination of 6-TG and budesonide, and 1 patient received 6-TG only. All patients improved remarkably. Normalisation of the thickened basement membrane was found in 2 patients and complete histological improvement including full recovery of villi was found in 1 patient. In the third patient, the thickened basement membrane was only very focally recognised. The thickened membrane persisted in the last patient, probably because of the short time of follow-up. CONCLUSIONS: CS should be separated from coeliac disease. Based on the lack of typical HLA phenotyping and the absence of coeliac-specific antibodies, there seems to be no relation with coeliac disease in these 4 cases. A promising treatment option might be 6-TG with or without budesonide. Research in a larger cohort is needed to standardise treatment for CS.

Long-Term Follow-Up of Transgender Women After Secondary Intestinal Vaginoplasty.

INTRODUCTION: Intestinal vaginoplasty with a sigmoid colon or ileal segment is an established surgical technique for vaginal reconstruction. Little has been reported on long-term (functional) outcome and postoperative quality of life. AIMS: To assess the surgical and long-term psychological outcomes of secondary intestinal vaginoplasty performed from 1970 through 2000 in transgender women. METHODS: Transgender women who underwent intestinal vaginoplasty from 1970 through 2000 were identified from our hospital registry. Demographics, surgical characteristics, complications, and reoperations were recorded. Traceable women were invited to fill out a set of questionnaires (quality-of-life questionnaire, Female Sexual Function Index, Amsterdam Hyperactive Pelvic Floor Scale for Women, Female Genital Self-Imaging Scale, and self-evaluation of vaginoplasty questionnaire) and attend the outpatient clinic for physical, endoscopic, and histologic examination of the neovagina. MAIN OUTCOME MEASURES: Primary outcomes were complications, reoperations, self-perceived quality of life, and functional and esthetic self-evaluation. RESULTS: Twenty-four transgender women were identified who underwent intestinal vaginoplasty as a secondary procedure from 1970 through 2000. There were no intraoperative complications. Three intestinal neovaginas were surgically removed because of postoperative complications. Nineteen women (79%) underwent at least one genital reoperation, most commonly introitus plasty (n = 13, 54%). Five women were deceased at time of analysis. Nine women consented to partake in the study (median age = 58 years, range = 50-73; median postoperative time = 29.6 years, range = 17.2-34.3). They were generally satisfied with life and scored 5.9 of 7 on a subjective happiness scale. Neovaginal functionality was rated as 7.3 and appearance as 7.4 of 10. CONCLUSION: In our institution, intestinal vaginoplasty before 2000 was always performed as a revision procedure after a previous vaginoplasty had failed. Although surgical corrections were frequently necessary, women reported satisfaction with the surgical outcome and with life in general.

Symptomatic HPV-related neovaginal lesions in transgender women: case series and review of literature.

OBJECTIVE: Worldwide, transgender women are an at-risk population for contracting sexually transmitted infections. Little information exists on symptoms and characteristics of neovaginal human papillomavirus (HPV) infections and associated diseases. We describe a case series of transgender women with symptomatic HPV-related neovaginal lesions and a review of current literature. METHODS: Transgender women with symptomatic HPV-related neovaginal lesions were identified from a departmental database comprising clinical and outpatient data on transgender women who underwent vaginoplasty between 1990 and 2015. HPV status was determined on excision and biopsy specimens by HPV DNA testing using GP5+6+-PCR and p16INK4A immunohistochemistry. Current literature was reviewed using the MEDLINE and EMBASE databases. RESULTS: This case series includes four transgender women with symptomatic, HPV-related neovaginal lesions. Two women presented with neovaginal and neovulvar pain and condylomata/leukoplakia, which were excised. These lesions showed moderate-to-severe dysplasia at histopathological examination, and were positive for high-risk HPV (hrHPV) and p16INK4A. Recurrence occurred in one patient and was treated with laser evaporation. Two women presented with neovaginal coital pain, neovaginal bleeding and condylomata. Neovulvar lesions were treated with podophyllotoxin. Neovaginal lesions were excised or evaporated. These lesions were low-risk HPV (lrHPV) positive. The literature search shows treatment options varying from conservative, topical podophyllotoxin to excision or laser evaporation under general anaesthesia. CONCLUSIONS: Neovaginal HPV infection can lead to benign condylomata (lrHPV) and various grades of dysplasia (hrHPV). We advise physicians to consider HPV infection and associated lesions in transgender women with otherwise unexplainable neovaginal pain or bleeding after vaginoplasty.

Spontaneous Gastric Perforation in a Case of Collagenous Gastritis.

Collagenous gastritis is an extremely rare disease, both in children and adults. Symptoms vary depending on the extent of collagenous changes in the bowel. In most of the children, iron deficiency anemia and abdominal pain are the presenting symptoms. We present a 15-year-old boy with acute abdomen due to gastric perforation the cause of which was collagenous gastritis.

Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma.

Cancer is fueled by deregulation of signaling pathways in control of cellular growth and proliferation. These pathways are also targeted by infectious pathogens en route to establishing infection. Gallbladder carcinoma (GBC) is frequent in the Indian subcontinent, with chronic Salmonella enterica serovar Typhi infection reported as a significant risk factor. However, direct association and causal mechanisms between Salmonella Typhi infection and GBC have not been established. Deconstructing the epidemiological association between GBC and Salmonella Typhi infection, we show that Salmonella enterica induces malignant transformation in predisposed mice, murine gallbladder organoids, and fibroblasts, with TP53 mutations and c-MYC amplification. Mechanistically, activation of MAPK and AKT pathways, mediated by Salmonella enterica effectors secreted during infection, is critical to both ignite and sustain transformation, consistent with observations in GBC patients from India. Collectively, our findings indicate that Salmonella enterica can promote transformation of genetically predisposed cells and is a causative agent of GBC.

[Non-responsive coeliac disease: what to do?]. / Als coeliakie niet beter wordt.

Coeliac disease (CD) is the most common cause of villous atrophy and is increasingly recognized. The majority of CD patients responds to a gluten-free diet (GFD). However, some patients experience persistence or recurrence of symptoms despite a GFD. These patients require further diagnostic workup. We describe a 62-year-old female with recurring symptoms attributed to refractory coeliac disease (RCD) type I. A 66-year-old patient with a similar history had aberrant intraepithelial lymphocytes characteristic for RCD type II in her duodenum. Furthermore, in a third CD patient described here, microscopic colitis was responsible for diarrhoea that persisted despite strict dietary adherence. Microscopic colitis is strongly associated with CD and should be considered in patients with this disease. On the basis of these three illustrative case studies, we discuss the causes of non-responsive CD and their respective diagnostic workup.