Vitamin D opposes multilineage cell differentiation induced by Notch inhibition and BMP4 pathway activation in human colon organoids.

Understanding the mechanisms involved in colonic epithelial differentiation is key to unraveling the alterations causing inflammatory conditions and cancer. Organoid cultures provide an unique tool to address these questions but studies are scarce. We report a differentiation system toward enterocytes and goblet cells, the two major colonic epithelial cell lineages, using colon organoids generated from healthy tissue of colorectal cancer patients. Culture of these organoids in medium lacking stemness agents resulted in a modest ultrastructural differentiation phenotype with low-level expression of enterocyte (KLF4, KRT20, CA1, FABP2) and goblet cell (TFF2, TFF3, AGR2) lineage markers. BMP pathway activation through depletion of Noggin and addition of BMP4 resulted in enterocyte-biased differentiation. Contrarily, blockade of the Notch pathway using the γ-secretase inhibitor dibenzazepine (DBZ) favored goblet cell differentiation. Combination treatment with BMP4 and DBZ caused a balanced strong induction of both lineages. In contrast, colon tumor organoids responded poorly to BMP4 showing only weak signals of cell differentiation, and were unresponsive to DBZ. We also investigated the effects of 1α,25-dihydroxyvitamin D3 (calcitriol) on differentiation. Calcitriol attenuated the effects of BMP4 and DBZ on colon normal organoids, with reduced expression of differentiation genes and phenotype. Consistently, in normal organoids, calcitriol inhibited early signaling by BMP4 as assessed by reduction of the level of phospho-SMAD1/5/8. Our results show that BMP and Notch signaling play key roles in human colon stem cell differentiation to the enterocytic and goblet cell lineages and that calcitriol modulates these processes favoring stemness features.

Clinico-Pathological Features, Outcomes and Impacts of COVID-19 Pandemic on Patients with Early-Onset Colorectal Cancer: A Single-Institution Experience.

BACKGROUND: The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC), as well as the impacts of COVID-19 pandemic. METHODS: We included all patients with pathologically confirmed diagnoses of CRC at Hospital Universitario La Paz from October 2016 to December 2021. The EOCRC cut-off age was 50 years old. RESULTS: A total of 1475 patients diagnosed with CRC were included, eighty (5.4%) of whom had EOCRC. Significant differences were found between EOCRC and later-onset patients regarding T, N stage and metastatic presentation at diagnosis; perineural invasion; tumor budding; high-grade tumors; and signet ring cell histology, with all issues having higher prevalence in the early-onset group. More EOCRC patients had the RAS/ BRAF wild type. Chemotherapy was administered more frequently to patients with EOCRC. In the metastatic setting, the EOCRC group presented a significantly longer median OS. Regarding the COVID-19 pandemic, more patients with COVID-19 were diagnosed with metastatic disease (61%) in the year after the lockdown (14 March 2020) than in the pre-pandemic EOCRC group (29%). CONCLUSIONS: EOCRC is diagnosed at a more advanced stage and with worse survival features in localized patients. More patients with EOCRC were diagnosed with metastatic disease in the year after the COVID-19 pandemic lockdown. The long-term consequences of COVID-19 are yet to be determined.

Compound Endoscopic Morphological Features for Identifying Non-Pedunculated Lesions ≥20 mm with Intramucosal Neoplasia.

BACKGROUND: The major limitation of piecemeal endoscopic mucosal resection (EMR) is the inaccurate histological assessment of the resected specimen, especially in cases of submucosal invasion. OBJECTIVE: To classify non-pedunculated lesions ≥20 mm based on endoscopic morphological features, in order to identify those that present intramucosal neoplasia (includes low-grade neoplasia and high-grade neoplasia) and are suitable for piecemeal EMR. DESIGN: A post-hoc analysis from an observational prospective multicentre study conducted by 58 endoscopists at 17 academic and community hospitals was performed. Unbiased conditional inference trees (CTREE) were fitted to analyse the association between intramucosal neoplasia and the lesions' endoscopic characteristics. RESULT: 542 lesions from 517 patients were included in the analysis. Intramucosal neoplasia was present in 484 of 542 (89.3%) lesions. A conditional inference tree including all lesions' characteristics assessed with white light imaging and narrow-band imaging (NBI) found that ulceration, pseudodepressed type and sessile morphology changed the accuracy for predicting intramucosal neoplasia. In ulcerated lesions, the probability of intramucosal neoplasia was 25% (95%CI: 8.3-52.6%; p < 0.001). In non-ulcerated lesions, its probability in lateral spreading lesions (LST) non-granular (NG) pseudodepressed-type lesions rose to 64.0% (95%CI: 42.6-81.3%; p < 0.001). Sessile morphology also raised the probability of intramucosal neoplasia to 86.3% (95%CI: 80.2-90.7%; p < 0.001). In the remaining 319 (58.9%) non-ulcerated lesions that were of the LST-granular (G) homogeneous type, LST-G nodular-mixed type, and LST-NG flat elevated morphology, the probability of intramucosal neoplasia was 96.2% (95%CI: 93.5-97.8%; p < 0.001). CONCLUSION: Non-ulcerated LST-G type and LST-NG flat elevated lesions are the most common non-pedunculated lesions ≥20 mm and are associated with a high probability of intramucosal neoplasia. This means that they are good candidates for piecemeal EMR. In the remaining lesions, further diagnostic techniques like magnification or diagnostic +/- therapeutic endoscopic submucosal dissection should be considered.

Comparative Study of Organoids from Patient-Derived Normal and Tumor Colon and Rectal Tissue.

Colon and rectal tumors, often referred to as colorectal cancer, show different gene expression patterns in studies that analyze whole tissue biopsies containing a mix of tumor and non-tumor cells. To better characterize colon and rectal tumors, we investigated the gene expression profile of organoids generated from endoscopic biopsies of rectal tumors and adjacent normal colon and rectum mucosa from therapy-naive rectal cancer patients. We also studied the effect of vitamin D on these organoid types. Gene profiling was performed by RNA-sequencing. Organoids from a normal colon and rectum had a shared gene expression profile that profoundly differed from that of rectal tumor organoids. We identified a group of genes of the biosynthetic machinery as rectal tumor organoid-specific, including those encoding the RNA polymerase II subunits POLR2H and POLR2J. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3/calcitriol upregulated stemness-related genes (LGR5, LRIG1, SMOC2, and MSI1) in normal rectum organoids, while it downregulated differentiation marker genes (TFF2 and MUC2). Normal colon and rectum organoids share similar gene expression patterns and respond similarly to calcitriol. Rectal tumor organoids display distinct and heterogeneous gene expression profiles, with differences with respect to those of colon tumor organoids, and respond differently to calcitriol than normal rectum organoids.

Accuracy of the Narrow-Band Imaging International Colorectal Endoscopic Classification System in Identification of Deep Invasion in Colorectal Polyps.

BACKGROUND & AIMS: T1 colorectal polyps with at least 1 risk factor for metastasis to lymph node should be treated surgically and are considered endoscopically unresectable. Optical analysis, based on the Narrow-Band Imaging International Colorectal Endoscopic (NICE) classification system, is used to identify neoplasias with invasion of the submucosa that require endoscopic treatment. We assessed the accuracy of the NICE classification, along with other morphologic characteristics, in identifying invasive polyps that are endoscopically unresectable (have at least 1 risk factor for metastasis to lymph node). METHODS: We performed a multicenter, prospective study of data collected by 58 endoscopists, from 1634 consecutive patients (examining 2123 lesions) at 17 university and community hospitals in Spain from July 2014 through June 2016. All consecutive lesions >10 mm assessed with narrow-band imaging were included. The primary end point was the accuracy of the NICE classification for identifying lesions with deep invasion, using findings from histology analysis as the reference standard. Conditional inference trees were fitted for the analysis of diagnostic accuracy. RESULTS: Of the 2123 lesions analyzed, 89 (4.2%) had features of deep invasion and 91 (4.3%) were endoscopically unresectable. The NICE classification system identified lesions with deep invasion with 58.4% sensitivity (95% CI, 47.5-68.8), 96.4% specificity (95% CI, 95.5-97.2), a positive-predictive value of 41.6% (95% CI, 32.9-50.8), and a negative-predictive value of 98.1% (95% CI, 97.5-98.7). A conditional inference tree that included all variables found the NICE classification to most accurately identify lesions with deep invasion (P < .001). However, pedunculated morphology (P < .007), ulceration (P = .026), depressed areas (P < .001), or nodular mixed type (P < .001) affected accuracy of identification. Results were comparable for identifying lesions that were endoscopically unresectable. CONCLUSIONS: In an analysis of 2123 colon lesions >10 mm, we found the NICE classification and morphologic features identify those with deep lesions with >96% specificity-even in non-expert hands and without magnification. ClinicalTrials.gov number NCT02328066.

Western view of the management of gastroesophageal foreign bodies.

The best modality for foreign body removal has been the subject of much controversy over the years. We have read with great interest the recent article by Souza Aguiar Municipal Hospital, Rio de Janeiro, Brazil, describing their experience with the management of esophageal foreign bodies in children. Non-endoscopic methods of removing foreign bodies (such as a Foley catheter guided or not by fluoroscopy) have been successfully used at this center. These methods could be an attractive option because of the following advantages: Shorter hospitalization time; easy to perform; no need for anesthesia; avoids esophagoscopy; and lower costs. However, the complications of these procedures can be severe and potentially fatal if not performed correctly, such as bronchoaspiration, perforation, and acute airway obstruction. In addition, it has some disadvantages, such as the inability to directly view the esophagus and the inability to always retrieve foreign bodies. Therefore, in Western countries clinical practice usually recommends endoscopic removal of foreign bodies under direct vision and with airway protection whenever possible.

Complicaciones neurológicas de la enfermedad de Wilson / Neurological complications of Wilson's disease

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[Neurological complications of inflammatory bowel disease]. / Complicaciones neurológicas de la enfermedad inflamatoria intestinal.

Although ulcerative colitis and Crohn's disease have traditionally been considered to be inflammatory diseases limited to the gastrointestinal tract, it has been shown that both pathologies are frequently accompanied by various extraintestinal disorders. There is an increasing evidence that they may also manifest in the nervous system, including the peripheral and the central parts. Although some of these neurological complications have been known for a long time, such as cerebrovascular disease, vasculitis and autoinmune processes including neuropathies and cerebral demyelination, others have been recently described. With the exception of some of this complications such as the thromboembolism, evidence for a casual relationship relies merely on single case reports or case series. In this article, we try to review the existing evidence on neurological manifestations of both variants of inflammatory bowel disease.

Complicaciones neurológicas de la enfermedad inflamatoria intestinal / Neurological complications of inflammatory bowel disease

Aunque la colitis ulcerosa y la enfermedad de Crohn se han considerado tradicionalmente como enfermedades limitadas a la mucosa del tubo digestivo, se ha demostrado que frecuentemente se acompañan de diferentes trastornos extraintestinales. Entre éstos, hay una evidencia creciente de que también se manifiestan en el sistema nervioso, tanto central como periférico. Aunque algunas de estas complicaciones neurológicas se conocen desde hace tiempo, como la enfermedad cerebrovascular, las vasculitis y los procesos de origen autoinmunitario, como las neuropatías o la desmielinización cerebral, otras sólo se han descrito recientemente. Con excepción de alguna de estas complicaciones, como la enfermedad tromboembólica, la mayoría de los datos de que disponemos proceden de casos clínicos individuales y series de casos. En este artículo pretendemos revisar la evidencia existente sobre las manifestaciones neurológicas de estas 2 variantes de la enfermedad inflamatoria intestinal

Although ulcerative colitis and Crohn's disease have traditionally been considered to be inflammatory diseases limited to the gastrointestinal tract, it has been shown that both pathologies are frequently accompanied by various extraintestinal disorders. There is an increasing evidence that they may also manifest in the nervous system, including the peripheral and the central parts. Although some of these neurological complications have been known for a long time, such as cerebrovascular disease, vasculitis and autoinmune processes including neuropathies and cerebral demyelination, others have been recently described. With the exception of some of this complications such as the thromboembolism, evidence for a casual relationship relies merely on single case reports or case series. In this article, we try to review the existing evidence on neurological manifestations of both variants of inflammatory bowel disease

Enfermedad de Whipple y sistema nervioso central / Whipple’s disease and central nervous system

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