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A novel histomolecular tumor of the central nervous system, the “intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive” has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological (clear cell morphology with signs of malignancy), clinical (with a dismal course with several recurrences, metastases and finally the patient’s death), genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology “IMT, FET-CREB fusion-positive”, and that further series of cases are needed to better characterize them.

The diagnosis of anaplastic meningioma (AM) (WHO grade III) is based on the presence of a high mitotic index (MI) and/or overt anaplasia. Only few data exist about the reproducibility and prognostic value of overt anaplasia. Additionally, the prognostic value of H3K27me3 loss in AM has not yet been demonstrated. Our objectives were to evaluate the reproducibility and prognostic value of WHO criteria and H3K27me3 loss in a multicenter series of 66 AM. Interobserver reproducibility was good for the determination of WHO grade (Kappa = 0.671) and MI (intraclass correlation coefficient [ICC] = 0.649), and fair for assessment of overt anaplasia (Kappa = 0.366). Patients with meningiomas showing high MI had significantly shorter overall survival (OS) than patients with meningiomas showing overt anaplasia without high MI (p = 0.009). OS was significantly lower in case of overt anaplasia with low MI (

Teduglutide (TED) reduces the need for parenteral support (PS) in patients with short-bowel syndrome with intestinal failure (SBS-IF). It is a glucagon-like peptide-2 analog that improves absorption, induces the expansion of the absorptive epithelium in the small intestine, and may be used in patients with SBS-IF after a 6- to 12-month adaptation period, if PS is always necessary. We described the functional and morphological effect of TED in a 40-year-old female patient with SBS-IF due to Crohn's disease who underwent terminal jejunostomy after 12 months of drug exposition. Marked hypertrophy of the villi was detected by endoscopic capsule and confirmed by histological measurements. This is the first publication demonstrating an increase in intestinal absorption in an SBS-IF patient treated with TED because of a morphological adaptation of the small bowel, with hyperplasia confirmed by capsule endoscopy and histology. The capsule endoscopy, a noninvasive exploration of the gut, could be evaluated to monitor the real efficacy of treatments with growth factors in SBS patients.

Background and Aims The prognosis of lymphoma that occurs in patients with inflammatory bowel disease [IBD] is poorly known. Methods A multicentre retrospective cohort analysis was done in seven French tertiary centres from 1999 to 2019. Only lymphoma occurring in patients with previous established diagnosis of IBD were analysed. The primary outcome was progression-free survival at 3 years. Results A total of 52 patients [male 65%, Crohn’s disease 79%, median age 48.3 years, median duration of IBD 10.1 years] were included, of whom 37 had been previously exposed to immunosuppressants and/or biologics for at least 3 months and 20 had primary intestinal lymphomas. The lymphoma histological types were: diffuse large B cell lymphomas [N = 17], Hodgkin lymphomas [N = 17], indolent B cell lymphomas [N = 12], and others including T cell lymphomas, mantle cell lymphomas, and unclassifiable B cell lymphoma [N = 6]. The median follow-up after lymphoma was 5.1 years (interquartile range [IQR] 4–7.8). Progression-free survival at 3 years was 85% in the overall population (95% confidence interval [CI] 75%–96%) with no significant difference between the exposed and unexposed group, 79% for patients exposed to immunosuppressants and/or biologics [95% CI 67%–94%], and 83% for patients diagnosed with primary intestinal lymphoma [95% CI 67%–100%]. No relapse of IBD has been observed during chemotherapy. The IBD relapse rate at the end of the last chemotherapy cycle was 23% at 3 years [95% CI 11%-39%] in the overall population. Conclusions In this large cohort, the prognosis for lymphomas occurring in IBD appears to be good and similar to what is expected, irrespective of the exposure to biologics and/or immunosuppressants.

INTRODUCTION: Magnetic resonance enterography (MRE) is useful for detecting bowel strictures, whereas a number of imaging biomarkers may reflect severity of fibrosis burden in Crohn's disease (CD). This study aimed to verify the association of MRE metrics with histologic fibrosis independent of inflammation. METHODS: This prospective European multicenter study performed MRE imaging on 60 patients with CD with bowel strictures before surgical resection. Locations of 61 histological samples were annotated on MRE examinations, followed by central readings using the Chiorean score and measurement of delayed gain of enhancement (DGE), magnetization transfer ratio, T2-weighted MRI sequences (T2R), apparent diffusion coefficient (ADC), and the magnetic resonance index of activity (MaRIA). Correlations of histology and MRE metrics were assessed. Least Absolute Shrinkage and Selection Operator and receiver operator characteristic (ROC) curve analyses were used to select composite MRE scores predictive of histology and to estimate their predictive value. RESULTS: ADC and MaRIA correlated with fibrosis (R = -0.71, P < 0.0001, and 0.59, P < 0.001) and more moderately with inflammation (R = -0.35, P < 0.01, and R = 0.53, P < 0.001). Lower or no correlations of fibrosis or inflammation were found with DGE, magnetization transfer ratio, or T2R. Least Absolute Shrinkage and Selection Operator and ROC identified a composite score of MaRIA, ADC, and DGE as a very good predictor of histologic fibrosis (ROC area under the curve = 0.910). MaRIA alone was the best predictor of histologic inflammation with excellent performance in identifying active histologic inflammation (ROC area under the curve = 0.966). DISCUSSION: MRE-based scores for histologic fibrosis and inflammation may assist in the characterization of CD stenosis and enable development of fibrosis-targeted therapies and clinical treatment of stenotic patients. ispartof: CLINICAL AND TRANSLATIONAL GASTROENTEROLOGY vol:13 issue:7 ispartof: location:United States status: published

International audience; Hepatic veno-occlusive disease (HVOD), alias sinusoidal obstruction syndrome, may develop as a complication of chemotherapy in the setting of hematopoietic stem cell transplantation. HVOD is less frequently described after exposure to chemotherapy in the nontransplant setting and can also be a complication after ingestion of toxins, such as pyrrolizidine alkaloids. Veno-occlusive disease may also affect the lungs, and it is therefore termed pulmonary veno-occlusive disease (PVOD). Similarly, PVOD can develop after exposure to chemotherapeutic agents in the treatment of solid and hematological malignancies. In addition, PVOD has also been linked to autoimmune disorders and occupational solvent exposure. Finally, the heritable form of PVOD is due to biallelic mutations of the EIF2AK4 gene. Both HVOD and PVOD share common histopathological features and pathophysiologic mechanisms. Both clinical disorders are rare complications that can appear after exposure to the common inciting trigger of chemotherapeutic agents. The present review aims to summarize the current knowledge of HVOD and PVOD and to describe both similarities as well as differences regarding both conditions.

Distinction of paraganglioma (PGL) from epithelial neuroendocrine tumors (NETs) can be difficult as they can mimic each other by nested architecture and expression of neuroendocrine markers. In this study we examined differential diagnostic markers in 262 PGLs (142 adrenal pheochromocytomas and 120 extra-adrenal PGLs), 9 duodenal gangliocytic PGLs and 3 cauda equina PGLs, and 286 NETs (81 GI, 78 pancreatic, 42 thoracic, 37 medullary thyroid carcinomas, and 48 high-grade NETs including 32 small cell carcinomas of lung). While keratin expression was nearly uniform in NETs with the exception of few tumors, extensive keratin expression was seen in only one PGL (90% of PGLs but only in 2% of NETs, usually focally. Tyrosine hydroxylase (TH) was expressed in >90% of adrenal, abdominal, and thoracic PGLs but only in 37% of head and neck PGLs reflecting their variable catecholamine synthesis. Focal or occasional extensive TH-expression was detected in 10% of NETs. CDX2 was a helpful discriminator seen in 28% of pancreatic and most GI NETs but in no PGLs. SOX10 detected sustentacular cells in 85% of PGLs and 7% of NETs, while GFAP detected sustentacular cells mainly in PGLs of neck and was absent in NETs. Duodenal gangliocytic PGLs (n = 9) and all cauda equina PGLs (n = 3) expressed keratins, lacked GATA3, showed no or minimal TH expression as some NETs, and contained SOX10 and S100 protein-positive spindle cells negative for GFAP. Ganglion-like epithelioid cells were keratin-positive and negative for TH and SOX10 differing from true ganglion cells. We conclude that duodenal gangliocytic and cauda equina PGLs have a NET-like immunoprofile and differ from ordinary PGLs. NETs can be distinguished from PGLs by their expression of keratins and general lack of GATA3, TH, and GFAP-positive sustentacular cells, and sometimes by expression of CDX2 or TTF1.

ObjectivePeritoneal or mesenteric tumours may correspond to several tumour types or tumour-like conditions, some of them being represented by histiocytosis. This rare condition often poses diagnostic difficulties that can lead to important time delay in targeted therapies. Our aim was to describe main features of histiocytoses with mesenteric localisation that can improve the diagnostic process.DesignWe performed a retrospective study on 22 patients, whose peritoneal/mesenteric biopsies were infiltrated by histiocytes.ResultsAbdominal pain was the revealing symptom in 10 cases, and 19 patients underwent surgical biopsies. The diagnosis of histiocytosis was proposed by initial pathologists in 41% of patients. The other initial diagnoses were inflammation (n=7), sclerosing mesenteritis (n=4) and liposarcoma (n=1). The CD163/CD68+CD1a- histiocytes infiltrated subserosa and/or deeper adipose tissues in 16 and 14 cases, respectively. A BRAFV600E mutation was detected within the biopsies in 11 cases, and two others were MAP2K1 mutated. The final diagnosis was histiocytosis in 18 patients, 15 of whom had Erdheim-Chester disease. The median diagnostic delay of histiocytosis was 9 months. Patients treated with BRAF or MEK inhibitors showed a partial response or a stable disease. One patient died soon after surgery, and five died by the progression of the disease.ConclusionDiagnosis of masses arising in the mesentery should be carefully explored as one of the possibilities in histiocytosis. This diagnosis is frequently missed on mesenteric biopsies. Molecular biology for detecting the mutations in BRAF or in genes of the MAP kinase pathway is a critical diagnostic tool.

Context The origin of tumor deposit in colorectal cancer is still unknown, and currently there is no single morphological feature to distinguish a metastatic lymph node from a tumor deposit. Histologically, the normal lymph node capsule and trabeculae contain a smooth muscular layer, which when present in extramural deposits would strongly suggest their lymph node origin. Objective We analyze the value of the smooth muscular layer criterion in reclassifying tumor deposit into metastatic lymph node. Design A total of 458 colo-rectal carcinomas surgical specimens treated or not by neoadjuvant (radio)chemotherapy were retrospectively included. Harvested tumor deposits were analyzed by Hematoxylin and Eosin and elastin staining on 10 consecutive serial sections and by α- smooth muscle actin immunostaining. Results A total of 129 tumor deposits were identified. 77 (60%) tumor deposits were reclassified into metastatic lymph node, of which 63 (49%) presented a smooth muscular layer on the initial Hematein Eosin staining and/or after serial tissue sections, confirmed by positive α-smooth muscle actin immunostaining in 43 out of 45 cases (90%). Fourteen (18%) additional tumor deposits were reclassified into metastatic lymph node by the appearance of lymphoid tissue after serial sections. Conclusions The presence of a smooth muscular layer in a presumable tumor deposit is helpful in pointing out its lymph node origin in patients with colo-rectal carcinomas. This criterion could improve the inter-observer agreement of tumor deposit identification, allowing accurate nodal staging and better assessment of patient's prognosis.

International audience; Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.

INTRODUCTION To investigate the factors associated with a delayed diagnosis (DD) of acute mesenteric ischemia (AMI). METHODS An observational cohort study from an intestinal failure center. The primary outcome was DD >24 hours. RESULTS Between 2006 and 2015, 74 patients with AMI were included and 39 (53%) had a DD. Plasma lactate

Background Ileal pouch-anal anastomosis (IPAA) is the standard of care after total proctocolectomy for ulcerative colitis (UC). However, inflammation often develops in the pouch, leading to acute or recurrent/chronic pouchitis (R/CP). MicroRNAs (miRNA) are used as accurate diagnostic and predictive biomarkers in many human diseases, including inflammatory bowel diseases. Therefore, we aimed to identify an miRNA-based biomarker to predict the occurrence of R/CP in patients with UC after colectomy and IPAA. Methods We conducted a retrospective study in 3 tertiary centers in France. We included patients with UC who had undergone IPAA with or without subsequent R/CP. Paraffin-embedded biopsies collected from the terminal ileum during the proctocolectomy procedure were used for microarray analysis of miRNA expression profiles. Deep neural network–based classifiers were used to identify biomarkers predicting R/CP using miRNA expression and relevant biological and clinical factors in a discovery cohort of 29 patients. The classification algorithm was tested in an independent validation cohort of 28 patients. Results A combination of 11 miRNA expression profiles and 3 biological/clinical factors predicted the outcome of R/CP with 88% accuracy (area under the curve = 0.94) in the discovery cohort. The performance of the classification algorithm was confirmed in the validation cohort with 88% accuracy (area under the curve = 0.90). Apoptosis, cytoskeletal regulation by Rho GTPase, and fibroblast growth factor signaling were the most dysregulated targets of the 11 selected miRNAs. Conclusions We developed and validated a computational miRNA-based algorithm for accurately predicting R/CP in patients with UC after IPAA.

The department of neuropathology of Sainte-Anne Hospital uses zinc-formalin as the fixative agent for its samples. No publication referenced in Pubmed has proven the validity of this fixative agent. In the context of the accreditation of our standard staining (HPS for Hemalun-Phloxin-Saffron), we started a file for the validation of this method in which the fixative agent constitutes an « interfering » substance which can modify the quality of the technique. The aim of this study was to prove that the use of zinc-formalin as a fixative agent is as suitable as the fixation with 4 % buffered formalin.A cohort of samples fixed by zinc-formalin and by 4 % buffered formalin was performed on fresh samples, then cut and stained by HPS. The slides were interpreted by three pathologists (one of them was outside our centre) ``blind '' to the fixative agent and they evaluated four criteria (general quality of the staining, components of the extracellular matrix, cytoplasmic details, and nuclear details) and scored them (from 0 to 3) according to the Association française en assurance qualité (AFAQAP) recommendations.The cohort included 43 samples. The results of the analysis showed that for samples fixed by zinc-formalin, three of the four criteria obtained significantly a better score than the samples fixed by classical formalin.Our results show that the zinc-formalin fixative does not constitute an ``interfering '' agent for the quality of the HPS staining for neuropathological samples.

Surgery is required in patients with symptoms of chronic radiation-induced enteritis (CRE) resistant to medical therapy. The study aimed to correlate histopathologic features of CRE to the clinical presentation and the postoperative recurrence.All patients with small bowel resection performed for CRE between 2006 and 2017 were studied. Histological data were retrospectively correlated to initial clinical data and to postoperative recurrence of CRE (occlusion, need for parenteral nutrition) observed during a median follow-up of 32 months.Forty-one patients were studied (39 women and 2 men, median age 62 yo at time of radiation for pelvic cancer, 80% gynecologic). Median time to surgery after radiation was 3 years. Ileocaecal resections (80% of patients) removed 60cm (median length). Histologically, a diffuse obliterative arteriopathy was present in 24 (59%) patients, highly associated to amyotrophy, villous atrophy and ulceration observed in 66, 63 and 34% of patients respectively (P.05). Diffuse arteriopathy was uncorrelated with patient's age and vascular risk factor (tobacco, diabetes, hypertension, dyslipidemia). Median time to surgery after radiation was longer in patients presenting with obliterative arteriopathy (13 years vs. 2.6 years, P=0.0002). During follow-up, half of the patients had a recurrence of CRE, uncorrelated to the arteriopathy.Radiation-induced enteritis requiring late surgery after radiation presented histologically with a diffuse obliterative arteriopathy and ischemic features. In our center, half of the patients were cured by surgery. The arterial injury was not a risk factor for postoperative recurrence.

Background 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type. Materials and Methods A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables. Results Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment. Conclusion Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy. Implications for Practice Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction.

The components of the hepatic vascular system (hepatic arteries, portal and hepatic veins, sinusoids, and lymphatics) can be damaged by various types of injury. Each of the resulting conditions is rare, which has limited knowledge and awareness. In the last two decades, international collaborations have allowed to reach critical masses of data, which has driven significant progresses in understanding and management of vascular disorders of the liver. The present paper discusses definitions, denominations, and diagnosis of such vascular disorders with the exception of those affecting hepatic arteries. Evolving pathogenic or pathophysiologic views relevant to the clinical aspects are also overviewed.

BACKGROUND: Following recent studies underlining the differences between de novo and secondary anaplastic meningiomas and the prognostic value of telomerase reverse transcriptase (TERT) promoter mutation, we decided to conduct a multicenter retrospective study to address these questions and determine specific prognostic factors in each of these 2 anaplastic meningioma subgroups. METHODS: Among the 68 meningioma cases initially selected, only 57 were confirmed as anaplastic meningiomas after centralized pathological review. TERT promoter mutation analysis was performed in all cases. RESULTS: Median overall survival was 2.6 years and 5-year survival rate was 10%. This study confirmed the better prognosis of de novo anaplastic meningiomas (28 tumors) compared with secondary anaplastic meningiomas (29 tumors) (P = 0.02). In the “de novo” group, meningiomas diagnosed on histological anaplasia alone had a better prognosis than those in patients with a high number of mitoses with or without anaplasia (P = 0.01). In the “secondary” group, tumors demonstrate very heterogeneous clinical courses leading to malignant transformation, and time to first relapse as a low-grade tumor was a strong predictor of overall survival (P = 0.0007). TERT promoter mutation in anaplastic meningiomas was rare (14%) and did not influence overall survival but was associated with a shorter recurrence-free survival in the secondary anaplastic meningioma subgroup (P = 0.02). The absence of TERT promoter methylation, although rare (3/33 cases), may be associated with prolonged overall survival (P = 0.02). CONCLUSION: This study highlights the different prognoses of de novo and secondary anaplastic meningiomas with specific prognostic factors in each subgroup. The analysis of TERT mutation and methylation could provide additional prognostic insights.

Background & aims Intestinal failure-associated liver disease is rare in adults and risk factors are unclear. The aim of this study was to determine risk factors of liver fibrosis in adults receiving home parenteral nutrition (HPN) for intestinal failure and its impact on survival. Methods We retrospectively analyzed patients with irreversible intestinal failure who underwent a liver biopsy between 2000 and 2013. Significant liver fibrosis was defined as ≥F2 according to NASH-CRN score. Results Thirty-two patients [46 years (29-60)] underwent liver biopsy 55 months (9-201) after beginning parenteral nutrition. Twenty-six patients (81%) had a short bowel (gut < 200cm), including 12 (37%) with an ultra-short bowel (gut

Aim Subtotal colectomy is the treatment of last resort in patients with severe colonic inertia (SCI) refractory to laxatives. Some studies have reported hypoplasia of the interstitial cells of Cajal (ICC) using a semi-quantitative analysis. The aims of this study were first to investigate if semi-quantitative or morphometry is better at the quantification of colonic ICC and secondly to determine whether there is a relationship between the number of ICC and the severity of constipation. Method Clinical and pathological data from patients with subtotal colectomy for SCI were collected. Quantification of ICC using CD117 immunohistochemistry and morphometric methods was performed at three different colonic sites in patients and controls. Results Twenty patients had a colectomy for SCI. All were considered to have failed maximal medical treatment and 45 % were hospitalized at least once for colonic obstruction due to faecaloma. Using a semi-quantitative methodology, 30 % of patients displayed ICC hypoplasia (< 7 per high power field (HPF)) and all controls had normal ICC. Using morphometry, the percentage of colonic ICC was significantly less in patients compared with controls with no significant differences between the ascending, transverse and descending colonic segments. Overall 60 % of patients had ICC hypoplasia (< 1% vs. 20 % of controls [p = 0.009]). The severity of constipation was not related to the quantity of ICC. Conclusion In patients with SCI, morphometric analysis is more sensitive than semi-quantitative analysis in the detection of ICC hypoplasia. The severity of constipation was not related to the quantity of ICC. This article is protected by copyright. All rights reserved.

Small bowel adenocarcinoma (SBA) complicating Crohn's disease (CD) is rare and generally found incidentally on surgical specimens. We report our experience in CD-associated SBA observed this last decade in a tertiary referral centre in order to update its incidence, clinical presentation and pathological features. All SBAs diagnosed in patients who underwent surgery for CD between 2006 and 2016 were retrospectively included. Clinico-pathological characteristics were reviewed, and follow-up was updated. SBA was diagnosed in 9 (1.7%) of 522 patients who underwent SB resection(s) after a median CD duration of 15 years [0-32]. The median age at diagnosis was 46 years. Seven (78%) patients had obstructive symptoms refractory to medical treatment. Pre-operative biopsy revealed neoplasia in five (56%) patients (dysplasia in three and SBA in two) justifying the surgery. Two (29%) of the seven patients with imaging had features suggestive of cancer. In all specimens, SBA developed in active ileitis with adjacent dysplasia. Stage I low-grade tubulo-glandular adenocarcinoma was observed in 33% of patients. Stage IV high-grade adenocarcinoma was observed in 56% of patients, and mucinous/signet ring cell differentiation predominated in 44% of patients. Molecular analysis showed no BRAF mutation, a KRAS mutation in one case and a microsatellite instability phenotype suggestive of Lynch syndrome in one case. After a median follow-up of 24 months [7-82], four (44%) patients died with advanced stage IV SBA. This surgical series confirms that CD-associated SBA is rare with an incidence of 1.7%. Adjacent dysplasia was present in all specimens and was identified before surgery in all patients who benefit from ileal biopsies. This strengthens the importance of screening all longstanding CD by endoscopy if surgery is not considered.

The formation of tertiary lymphoid organs (TLOs) is orchestrated by the stromal cells of tissues chronically submitted to inflammatory stimuli, in order to uphold specific adaptive immune responses. We have recently shown that the smooth muscle cells of the arterial wall orchestrate the formation of the TLOs associated with atherosclerosis in response to the local release of TNF-α. Observational studies have recently documented the presence of structures resembling TLOs the creeping fat that develops in the mesentery of patients with Crohn's disease (CD), an inflammatory condition combining a complex and as yet not elucidated infectious and autoimmune responses. We have performed a comprehensive analysis of the TLO structures in order to decipher the mechanism leading to their formation in the mesentery of CD patients, and assessed the effect of infectious and/or inflammatory inducers on the potential TLO-organizer functions of adipocytes. Quantitative analysis showed that both T and B memory cells, as well as plasma cells, are enriched in the CD-affected mesentery, as compared with tissue from control subjects. Immunohistochemistry revealed that these cells are concentrated within the creeping fat of CD patients, in the vicinity of transmural lesions; that T and B cells are compartmentalized in clearly distinct areas; that they are supplied by post-capillary high endothelial venules and drained by lymphatic vessels indicating that these nodules are fully mature TLOs. Organ culture showed that mesenteric tissue samples from CD patients contained greater amounts of adipocyte-derived chemokines and the use of the conditioned medium from these cultures in functional assays was able to actively recruit T and B lymphocytes. Finally, the production of chemokines involved in TLO formation by 3T3-L1 adipocytes was directly elicited by a combination of TNF-α and LPS in vitro. We therefore propose a mechanism in which mesenteric adipocyte, through their production of key chemokines in response to inflammatory/bacterial stimuli, may orchestrate the formation of functional TLOs developing in CD-affected mesentery.

It remains unclear whether the classic imaging criteria for the non-invasive diagnosis of hepatocellular carcinoma (HCC) can be applied to chronic vascular liver diseases, such as Budd-Chiari syndrome (BCS). Herein, we aimed to evaluate the diagnostic value of washout for the discrimination between benign and malignant lesions in patients with BCS.This retrospective study included all patients admitted to our institution with a diagnosis of BCS and focal lesions on MRI from 2000 to 2016. MRI images were reviewed by 2 radiologists blinded to the nature of the lesions. Patient and lesion characteristics were recorded, with a focus on washout on portal venous and/or delayed phases. Lesions were compared using Chi-square, Fisher's, Student's t or Mann-Whitney U tests.A total of 49 patients (mean age 35 ± 12 years; 34 women [69%] and 15 men [31%]) with 241 benign lesions and 12 HCC lesions were analyzed. Patients with HCC were significantly older (mean age 44 ± 16 vs. 33 ± 9 years, p = 0.005), with higher alpha-fetoprotein (AFP) levels (median 16 vs. 3 ng/ml, p = 0.007). Washout was depicted in 9/12 (75%) HCC, and 69/241 (29%) benign lesions (p0.001). A total of 52/143 (36%) lesions ≥1 cm with arterial hyperenhancement showed washout (9 HCC and 43 benign lesions). In this subgroup, the specificity of washout for the diagnosis of HCC was 67%. Adding T1-w hypointensity raised the specificity to 100%. A serum AFP15 ng/ml was associated with 95% specificity.Washout was observed in close to one-third of benign lesions, leading to an unacceptably low specificity for the diagnosis of HCC. The non-invasive diagnostic criteria proposed for cirrhotic patients cannot be extrapolated to patients with BCS.Washout on MRI is depicted in a significant proportion of benign nodules in patients with Budd-Chiari syndrome (BCS), limiting its value for the differentiation between benign and malignant lesions. Criteria proposed for the non-invasive diagnosis of hepatocellular carcinoma in patients with cirrhosis cannot be extrapolated to patients with BCS. Additional imaging findings and patient characteristics, including alpha-fetoprotein serum level, can help determine the probability of a nodule being HCC in patients with BCS.

International audience; Background and AimsDifferent types of histologic lesions at the ileal margin, detected by histology, have been associated with increased rates of recurrence after ileocaecal surgery in patients with Crohn’s disease (CD). We aimed to characterize histologic features of the ileal margin and to evaluate their association with disease recurrence.MethodsWe collected histologic data from 211 patients with ileal or ileocolonic CD who underwent ileocolonic resections at hospitals in France from September 2010 through December 2016. Ileal margins were analyzed. Early endoscopic recurrence was defined by a Rutgeerts score of i2 or more, 6 months after surgery. We also collected data from 10 adults with healthy ileum who underwent ileocecal resection for colonic tumors (controls). Clinical relapse was defined by CD-related symptoms confirmed by imaging, endoscopy, therapy intensification, CD-related complication, or subsequent surgery.ResultsSix months after surgery, 49% of patients had endoscopic recurrence; 5 years after surgery, 57% of patients had clinical relapse. Ileal margins were macroscopically affected in 20.9% of patients. CD transmural lesions at the margin (defined by mucosal ulceration or cryptitis, submucosal fibrosis and lymphoplasmacytic infiltrate of the subserosa) were observed in 13.6% of patients. Endoscopic recurrence was observed in 75% of patients with CD transmural lesions vs 46% of patients without (P =.005). In multivariate analysis, CD transmural lesions at the margin were independently associated with early endoscopic recurrence (OR, 3.83; 95% CI, 1.47-11.05; P =.008) and clinical recurrence (OR 2.04; 95% CI, 1.09-3.99; P =.026).ConclusionIn patients with CD, transmural lesions at the ileal margin were associated with an increased risk of post-operative recurrence. Histologic features of the ileal margin should be included in making decisions about post-operative therapy.

To identify treatments likely to prevent progression towards irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI). Prospective observational cohort study from a French intestinal stroke center. Multivariate analysis using a time-dependent Cox regression model. Between 2009 and 2015, 67 patients with AMI were included. ITIN occurred in 34% of patients and mortality was 13%. Oral antibiotics was independently associated with a decreased risk of ITIN (HR: 0.16 (95% CI = 0.03–0.62); p = 0.01). By decreasing luminal bacterial load and translocation, oral antibiotics in addition to early revascularization might reduce progression of AMI to ITIN.

Clinical presentation A pregnant woman (third trimester) presented with intense abdominal pain, nausea and myalgia. The patient was obese (body mass index 38) and was being treated for high blood pressure, hyperuricemia and hypothyroidism. She had chronic renal deficiency related to focal segmental glomerular sclerosis requiring dialysis. The physical examination at admission revealed a fever of 39°C and an acute abdomen with abdominal guarding in the right upper quadrant without hepatomegaly or splenomegaly. There were no clinical signs of pre-eclampsia. Fetal ultrasound and a Doppler of the umbilical vessels were normal. Laboratory tests showed normal liver and liver function (total protein 95%, alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin normal). The white cell count was 10×10 9 /l (90% neutrophils), with a normal platelet count. Blood, urine and vaginal cultures were negative. Abdominal ultrasound revealed isolated thickening of the gallbladder wall without cholelithiasis. Empirical antibiotic treatment was begun with intravenous amoxicillin. Six days later, the patient9s condition had worsened with increased abdominal pain, persistent fever and liver test abnormalities (AST–ALT 6N). However, bilirubin, hepatic synthesis tests, as well as leucocyte and platelet counts were still normal. A caesarean section followed by coelioscopy was decided. Coelioscopy revealed a liver with numerous necrotic spots (see figure 1). Question What is the diagnosis?

Background Gastrointestinal complications are the main cause of death in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Available treatments often restore biochemical homeostasis, but fail to cure gastrointestinal symptoms. Methods We evaluated the small intestine neuromuscular pathology of an untreated MNGIE patient and two recipients of hematopoietic stem cells, focusing on enteric neurons and glia. Additionally, we evaluated the intestinal neuromuscular pathology in a mouse model of MNGIE treated with hematopoietic stem cell gene therapy. Quantification of muscle wall thickness and ganglion cell density was performed blind to the genotype with ImageJ. Significance of differences between groups was determined by two-tailed Mann-Whitney U test (P

The current paradigm in the pathogenesis of several hemolytic red blood cell disorders is that reduced cellular deformability is a key determinant of splenic sequestration of affected red cells. Three distinct features regulate cellular deformability: membrane deformability, surface area-to-volume ratio (cell sphericity), and cytoplasmic viscosity. By perfusing normal human spleens ex vivo, we had previously showed that red cells with increased sphericity are rapidly sequestered by the spleen. Here, we assessed the retention kinetics of red cells with decreased membrane deformability but without marked shape changes. A controlled decrease in membrane deformability (increased membrane rigidity) was induced by treating normal red cells with increasing concentrations of diamide. Following perfusion, diamide-treated red blood cells (RBCs) were rapidly retained in the spleen with a mean clearance half-time of 5.9 minutes (range, 4.0-13.0). Splenic clearance correlated positively with increased membrane rigidity (r = 0.93; P < .0001). To determine to what extent this increased retention was related to mechanical blockade in the spleen, diamide-treated red cells were filtered through microsphere layers that mimic the mechanical sensing of red cells by the spleen. Diamide-treated red cells were retained in the microsphilters (median, 7.5%; range, 0%-38.6%), although to a lesser extent compared with the spleen (median, 44.1%; range, 7.3%-64.0%; P < .0001). Taken together, these results have implications for understanding the sensitivity of the human spleen to sequester red cells with altered cellular deformability due to various cellular alterations and for explaining clinical heterogeneity of RBC membrane disorders.

Yersinia are common contaminants of food products, but their prevalence in the human gut is poorly documented. Yersinia have been implicated in Crohn's Disease (CD, an inflammatory bowel disease) however their role in CD is controversial. We performed highly sensitive PCR assays of specific sequences for the gyrB gene of Y. aldovae, Y. bercovieri, Y. enterocolitica, Y. intermedia, Y. mollaretii and the inv gene of Y. pseudotuberculosis. We analyzed a total of 470 ileal samples taken from 338 participants (262 CD patients and 76 controls) belonging to three independent cohorts. All patients and controls were phenotyped and genotyped for the main CD susceptibility variants: NOD2, ATG16L1, and IRGM. Yersinia were found in 7.7% of ileal samples (respectively 7.9 and 7.6% in controls and CD patients) corresponding to 10% of participants (respectively 11.8 and 9.5% in controls and CD patients). Y. enterocolitica, Y. pseudotuberculosis and Y. intermedia were the most frequently identified species. The bacteria were more frequent in resected specimens, lymph nodes and Peyer's patches. Yersinia were no more likely to be detected in CD tissues than tissues from inflammatory and non-inflammatory controls. CD patients treated with immunosuppressants were less likely to be Yersinia carriers. In conclusion, this work shows that Yersinia species are frequently found at low levels in the human ileum in health and disease. The role of Yersinia species in this ecosystem should now be explored.

The therapeutic management of malignant colorectal polyp with endoscopic resection is mainly based on specific histopathological criteria. The quality of these criteria is strongly linked to the management of the endoscopic specimen. The French Pathology Society drafted a standardized pathological report with guidelines for the macroscopic management of the endoscopic specimen and explanatory notes for each histopathological criteria. These guidelines are based on the TNM AJCC/UICC classification, 8th edition and the WHO 2010 classification of colorectal tumors, the recommendations of the French Society of Digestive Endoscopy, the synthesis of the literature and on international consensus for prognostic criteria. The pathological report of a malignant colorectal polyp must clearly mention: the histological type and the size of the polyp, the pT stage and the following five prognostic criteria: the value of the resection margins, the level of tumor invasion into the submucosa, the grade of the tumor, the absence or presence of vascular emboli and of tumor budding.

Background & Aims Acute severe ulcerative colitis (ASUC) is a life-threatening condition managed with intravenous steroids followed by infliximab, cyclosporine, or colectomy (for patients with steroid resistance). There are no biomarkers to identify patients most likely to respond to therapy; ineffective medical treatment can delay colectomy and increase morbidity and mortality. We aimed to identify biomarkers of response to medical therapy for patients with ASUC. Methods We performed a retrospective analysis of 47 patients with ASUC, well characterized for their responses to steroids, cyclosporine, or infliximab, therapy at 2 centers in France. Fixed colonic biopsies, collected before or within the first 3 days of treatment, were used for microarray analysis of microRNA expression profiles. Deep neural network-based classifiers were used to derive candidate biomarkers for discriminating responders from non-responders to each treatment and to predict which patients would require colectomy. Levels of identified microRNAs were then measured by quantitative PCR analysis in a validation cohort of 29 independent patients—the effectiveness of the classification algorithm was tested on this cohort. Results A deep neural network-based classifier identified 9 microRNAs plus 5 clinical factors, routinely recorded at time of hospital admission, that associated with responses of patients to treatment. This panel discriminated responders to steroids from non-responders with 93% accuracy (area under the curve, 0.91). We identified 3 algorithms, based on microRNA levels, that identified responders to infliximab vs non-responders (84% accuracy, AUC = 0.82) and responders to cyclosporine vs non-responders (80% accuracy, AUC = 0.79). Conclusion We developed an algorithm that identifies patients with ASUC who respond vs do not respond to first- and second-line treatments, based on microRNA expression profiles in colon tissues.

Inflammatory hepatocellular adenomas (IHCA), which accounts for 40% to 50% of all hepatocellular adenomas are characterized by the activation of the IL6/JAK/STAT pathway. We herein report the case of a 52-year-old woman presenting with severe multiple typical IHCA that regressed dramatically on treatment with fenofibrate, a PPAR agonist known to prevent IL6-induced inflammation experimentally and in humans. Further similar observations are needed to ascertain the potential benefit of this therapeutic approach for large or unresectable IHCA.

Extension of ampulloma into the lower common bile duct (CBD) is observed in up to 30% of cases. This biliary extension can prevent complete tumor resection thus is considered as a contraindication for endoscopic and even surgical ampullectomy. For ampullomas associated with a prolonged biliary extension, a pancreaticoduodenectomy is associated with a high morbidity and can be considered as an overtreatment for a benign neoplasm. The present study describes a new surgical approach including ampullectomy with complete resection of the intrapancreatic CBD and restoration of both biliary and pancreatic flow by two separate anastomoses. This procedure was performed in seven patients for a non-invasive ampulloma with a 25- to 70-mm CBD involvement. No patients died and three developed postoperative complications. Resection was R0 in all patients but one. With a 24-month median follow-up (range = 3–84), no patients developed pancreatic insufficiency or tumor recurrence.

Backgrounds and Aims: The effect of cigarette smoking [CS] is ambivalent since smoking improves ulcerative colitis [UC] while it worsens Crohn’s disease [CD]. Although this clinical relationship between inflammatory bowel disease [IBD] and tobacco is well established, only a few experimental works have investigated the effect of smoking on the colonic barrier homeostasis focusing on xenobiotic detoxification genes. Methods: A comprehensive and integrated comparative analysis of the global xenobiotic detoxification capacity of the normal colonic mucosa of healthy smokers [ n = 8] and non-smokers [ n = 9] versus the non-affected colonic mucosa of UC patients [ n = 19] was performed by quantitative real-time polymerase chain reaction [qRT PCR]. The detoxification gene expression profile was analysed in CD patients [ n = 18], in smoking UC patients [ n = 5], and in biopsies from non-smoking UC patients cultured or not with cigarette smoke extract [ n = 8]. Results: Of the 244 detoxification genes investigated, 65 were dysregulated in UC patients in comparison with healthy controls or CD patients. The expression of ≥ 45/65 genes was inversed by CS in biopsies of smoking UC patients in remission and in colonic explants of UC patients exposed to cigarette smoke extract. We devised a network-based data analysis approach for differentially assessing changes in genetic interactions, allowing identification of unexpected regulatory detoxification genes that may play a major role in the beneficial effect of smoking on UC. Conclusions: Non-inflamed colonic mucosa in UC is characterised by a specifically altered detoxification gene network, which is partially restored by tobacco. These mucosal signatures could be useful for developing new therapeutic strategies and biomarkers of drug response in UC.

Background: Mesenteric panniculitis (MP) is mostly an associated sign of an intra-abdominal or systemic inflammatory primary disease. Nevertheless, etiological and differential diagnosis of idiopathic MP can be challenging when an associate primary cause is not in the foreground. Methods: We report here the case of an isolated small bowel Crohn's disease, long time considered as idiopathic MP. Results: This patient presented to our department with a 10-year history of acute abdominal symptoms evolving with flare-up and remission. A diagnosis of idiopathic MP was made based on compatible CT-scan features along with normal laboratory tests and upper and lower bowel endoscopies. As symptoms recurred, a steroid course was proposed which dramatically improved his condition for years. Finally, an explorative laparoscopy was performed because of concern of malignancy when he returned to our unit with a steroid refractory flare-up and weight loss, along with MP nodes growing up to 10 mm. Crohn's disease was eventually diagnosed, based on histopathological middle-gut bowel resection and numerous granulomas in mesenteric nodes without necrosis. Conclusion: This case emphasizes the importance of excluding inflammatory intestinal lesions before making the diagnosis of idiopathic MP (fecal calprotectin, magnetic resonance enterography, wireless capsule endoscopy).

Background Aside from cases of backwash ileitis, the ileal mucosa of patients with ulcerative colitis (UC), an idiotypic inflammatory bowel disease, has received little attention despite the fact that colitis is known to trigger alterations in morphology and/or functions of the small intestine remotely. Methods The ileal mucosa was studied in patients with UC and in a spontaneous model of colitis (Il10/Nox1 dKO mice) mimicking the histological and clinical features of UC and was also studied in acute and chronic murine models of chemically induced colitis. Proliferation and apoptosis were assessed using morphological and immunohistological methods and Western blot analysis. Peyer's patch immune cell subsets were analyzed. Cytokines levels were quantified using quantitative PCR and Luminex xMAP technology. Total RNA from isolated ileal crypts was used for whole genome transcriptome analysis. Results The most striking features were an increased ileal crypt length associated with an enhanced cell proliferation of the transit-amplifying cells along with activation of the Wnt/β-catenin and MAPkinase pathways. These changes did not result from intestinal inflammation as assessed by histology and/or pro-inflammatory cytokine expression levels. The increased proliferation rate was dependent on the duration but not on the severity of colitis and was observed in different mouse models of colitis, including the Il10/Nox1 dKO model and 2,4,6-trinitrobenzenesulfonic acid-treated mice. Interestingly, the ileal mucosa of patients with UC also displayed longer crypts and enhanced cell proliferation compared with control patients. Conclusions These data show that despite the absence of inflammation in the small intestine, alterations in the ileal mucosa homeostasis are present in UC. Copyright © 2016 Crohn's and Colitis Foundation of America, Inc.

International audience; BackgroundUlcerative colitis (UC) promotes cancer, and can be ameliorated by early appendicectomy for appendicitis. The aim of the study was to explore the effect of appendicectomy on colitis and colonic neoplasia in an animal model of colitis and a cohort of patients with UC. MethodsFive-week old IL10/Nox1(DKO) mice with nascent colitis and 8-week-old IL10/Nox1(DKO) mice with established colitis underwent appendicectomy (for experimental appendicitis or no appendicitis) or sham laparotomy. The severity and extent of colitis was assessed by histopathological examination, and a clinical disease activity score was given. From a cohort of consecutive patients with UC who underwent colectomy, the prevalence of appendicectomy and pathological findings were collected from two institutional databases. ResultsAppendicectomy for appendicitis ameliorated experimental colitis in the mice; the effect was more pronounced in the 5-week-old animals. Appendicectomy in the no-appendicitis group was associated with an increased rate of colonic high-grade dysplasia (HGD) or cancer compared with rates in sham and appendicitis groups (13 of 20 versus 0 of 20 and 0 of 20 respectively; P < 0001). Fifteen of 232 patients who underwent colectomy for UC had previously had an appendicectomy, and nine of these had colonic cancer or HGD. Thirty (138 per cent) of 217 patients with the appendix insitu had colonic neoplastic lesions. Multivariable analysis showed that previous appendicectomy was associated with colorectal neoplasia (odds ratio 1688, 95 per cent c.i. 332 to 11269). ConclusionAppendicectomy for experimental appendicitis ameliorated colitis. The risk of colorectal neoplasia appeared to increase following appendicectomy without induced appendicitis in a mouse model of colitis, and in patients with UC who had undergone appendicectomy. Surgical relevance Appendicectomy for appendicitis protects against UC. In this murine model of colitis, appendicectomy for experimental appendicitis protected against colitis, but appendicectomy without appendicitis promoted colorectal carcinogenesis. In patients with ulcerative colitis who underwent colectomy, absence of the appendix (proof of previous appendicectomy) in the resection specimen was independently associated with colorectal neoplasia. Although patients with UC and a history of appendicectomy represent a small subset, they may need closer monitoring for colorectal neoplasia. Appendicectomy reduces inflammation, increases risk for cancer

Although meningioma is a frequent intracranial tumor, it rarely affects the geniculate ganglion of the facial nerve. Facial palsy is the most common symptom. When hearing is preserved (class A or B, AAO-HNS), tumor is best removed through a middle cranial fossa approach. We report the case of a geniculate ganglion meningioma and present its clinical, radiological, and pathological features. Surgical management is discussed. A literature review revealed that only 17 previous cases have been reported during the last 50 years.

Background & Aims The aim of this study was to evaluate the specificity of the infiltration of digestive tract mucosa by immunoglobulin (Ig) G4–positive plasma cells in patients with autoimmune pancreatitis (AIP), as compared with normal or inflammatory mucosa. Methods Plasma cell infiltration, CD138 and IgG4 immunostaining of digestive biopsies were compared in 4 groups of patients: AIP type 1 (n = 19); AIP type 2 (n = 4) with inflammatory bowel disease (IBD); IBD without pancreatic disorders (n = 20); and controls (n = 26). Results With AIP type 1 versus controls, more plasma cells were present in the gastric mucosa of AIP (P = .02) without difference concerning IgG4+ plasma cells at any biopsy site. With AIP type 1 versus IBD, colonic mucosa was more often abnormal (P = .004), and more CD138 (P = .02) and IgG4 plasma cells (P = .0002) were counted in the colon biopsies of IBD. With AIP type 2 versus IBD, no difference for plasma cell and IgG4 infiltration was found. Conclusions IgG4-positive plasma cells are not more numerous in the digestive mucosa of AIP patients than in controls, but they are more abundant in the colon of IBD patients than in AIP patients.

The ability to predict response after chemoradiotherapy in rectal adenocarcinoma may allow selecting patients to whom less invasive surgical treatment could be proposed. Tumor hypoxia has been implicated in the mechanisms of resistance to chemoradiotherapy in several malignancies. The aim was to identify morphological criteria and molecular markers of hypoxia associated with chemoradiotherapy response. Clinicopathologic data from 61 patients (35 male, 60.5 ± 10 years) undergoing rectal cancer resection after neoadjuvant chemoradiotherapy were collected. Pretreatment biopsies, available for 40 patients, were immunostained for hypoxia markers (carbonic anhydrase 9, glucose transporter 1, chemokine receptor 4) and microvascular density determination. Mean tumor size was 2.7 ± 1.6 cm. Twenty-one patients (34%) were considered as responders, that is, having significant or complete primary tumor regression without lymph node metastasis. Compared to other patients, responders had significantly more often flat tumors with or without ulceration (57% versus 18%, P = .01) and less vascular and/or neural invasions (9% versus 65%, P < .0001) or tumor necrosis (9% versus 41%, P < .01), respectively. Regarding pretreatment biopsies, carbonic anhydrase 9 expression was significantly lower in responders (7% versus 46%, P = .012). This study showed that tumor necrosis as an overexpression of carbonic anhydrase 9 was an effective molecular marker of postchemoradiotherapy response. This might suggest a key role of hypoxia in resistance mechanisms of chemoradiotherapy in rectal adenocarcinoma. This study highlighted the importance of predictive criteria to chemoradiotherapy response in proposing to selected patients an alternative treatment (eg, local resection) to more radical surgery.

Background & Aims Ulcerative colitis (UC) is a chronic inflammatory disorder that affects the colonic epithelium. Epidemiology studies indicate an environmental component is involved in pathogenesis, although the primary changes in the digestive epithelium that cause an uncontrolled inflammatory response are not known. Animal studies have shown that altered endoplasmic reticulum (ER) stress response initiates intestinal inflammation in epithelial tissues, but abnormalities associated with ER stress have not been identified in patients with UC. Methods Using immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence analyses, we assessed ER stress signaling in uninflammed colonic mucosa from patients with UC and controls. Genome-wide microarray analysis of actively translated polysome-bound messenger RNA was performed using samples of unaffected mucosa from patients with UC, and data were compared with those from controls. Results Inositol-requiring kinase and activating transcription factor signaling pathways were activated in inactive colonic epithelium from patients with UC; these mediate proinflammatory and regenerative responses. Blocking phosphorylation of the translation initiation factor 2 (eIF2α), which mediates the integrated stress response, deregulated initiation of translation and reduced the numbers of stress granules in colonic epithelial cells from patients with UC. Genome-wide microarray analysis of actively translated, polysome-bound messenger RNA from patients revealed changes in protein translation that altered colonic epithelial barrier function (levels of detoxification and antioxidant enzymes and proteins that regulate the cell cycle, cell-cell adhesion, and secretion), compared with controls. Conclusions Colonic mucosa samples from patients with UC have defects in the eIF2α pathway that controls protein translation and the cell stress response. This pathway might be investigated to identify new therapeutic targets for patients with UC.

International audience; ABSTRACT The homeostatic self-renewal of the colonic epithelium requires coordinated regulation of the canonical Wnt/β-catenin and Notch signaling pathways to control proliferation and lineage commitment of multipotent stem cells. However, the molecular mechanisms by which the Wnt/β-catenin and Notch1 pathways interplay in controlling cell proliferation and fate in the colon are poorly understood. Here we show that NADPH oxidase 1 (NOX1), a reactive oxygen species (ROS)-producing oxidase that is highly expressed in colonic epithelial cells, is a pivotal determinant of cell proliferation and fate that integrates Wnt/β-catenin and Notch1 signals. NOX1-deficient mice reveal a massive conversion of progenitor cells into postmitotic goblet cells at the cost of colonocytes due to the concerted repression of phosphatidylinositol 3-kinase (PI3K)/AKT/Wnt/β-catenin and Notch1 signaling. This conversion correlates with the following: (i) the redox-dependent activation of the dual phosphatase PTEN, causing the inactivation of the Wnt pathway effector β-catenin, and (ii) the downregulation of Notch1 signaling that provokes derepression of mouse atonal homolog 1 (Math1) expression. We conclude that NOX1 controls the balance between goblet and absorptive cell types in the colon by coordinately modulating PI3K/AKT/Wnt/β-catenin and Notch1 signaling. This finding provides the molecular basis for the role of NOX1 in cell proliferation and postmitotic differentiation.

Common sites of colorectal breast carcinoma metastasis are bones, lungs, the central nervous system and the liver. Metastases in the gastrointestinal (GI) tract are rare and especially involve the stomach rather than the colon. Clinical or radiological features usually cannot differentiate them from a primary colorectal tumor, resulting in inappropriate treatment. In some cases, this lesion suggests multifocal spread of breast cancer with peritoneal carcinomatosis. Colorectal breast cancer metastasis is a rare finding and there is no consensus on the management of these lesions. The present case report describes a 69-year-old female with metastatic breast cancer presenting as an obstructive tumor of the transverse colon.