Clinical approach for managing patients with unexpected CDH1 mutations: A case report.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy. METHODS: Germline DNA, obtained from peripheral blood, was analysed by NGS. RESULTS: A 47-year-old woman was diagnosed with high-grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut-off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow-up. CONCLUSION: This case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.

Implementación de la disección endoscópica submucosa esofágica en España: resultados del registro nacional / Implementation of esophageal endoscopic submucosal dissection in Spain: Results from the nationwide registry

Introducción y objetivos Los resultados de la disección submucosa endoscópica (DSE) en el esófago no han sido evaluados en nuestro país. Nuestro objetivo principal fue analizar la efectividad y la seguridad de la técnica. Material y métodos Análisis del registro nacional prospectivo de DSE. Se incluyeron todas las lesiones superficiales esofágicas extirpadas mediante DSE en 17 hospitales (20 endoscopistas) entre enero de 2016 y diciembre de 2021. Se excluyeron las lesiones subepiteliales. La variable principal fue el porcentaje de resección curativa. Se realizó un análisis de regresión logística para conocer los predictores de resección no curativa y un análisis de supervivencia. Resultados Se realizaron un total de 102 DSE en 96 pacientes. El éxito técnico fue del 100% y el porcentaje de resección en bloque, del 98%. El porcentaje de resección R0 y curativa fue del 77,5% (n = 79; IC 95%: 68%-84%) y del 63,7% (n = 65; IC 95%: 54%-72%), respectivamente. La histología más frecuente fue la neoplasia sobre esófago de Barrett (n = 55 [53,9%]). El principal motivo de resección no curativa fue la invasión submucosa profunda (n = 25). Los centros con menor volumen de casos obtuvieron cifras inferiores de resección curativa. El porcentaje de perforación, sangrado diferido y estenosis posprocedimiento fue del 5%, del 5% y del 15,7%, respectivamente. Ningún paciente falleció ni requirió cirugía por un efecto adverso. Tras una mediana de seguimiento de 14 meses, 20 pacientes (20,8%) recibieron cirugía y/o quimio-radioterapia, y 9 fallecieron (mortalidad del 9,4%). Conclusiones En nuestro medio, la DSE esofágica es curativa en aproximadamente dos de cada tres pacientes, con un riesgo aceptable de efectos adversos (AU)

Introduction and aims The outcomes of endoscopic submucosal dissection (ESD) in the esophagus have not been assessed in our country. Our primary aim was to analyze the effectiveness and safety of the technique. Material and methods Analysis of the prospectively maintained national registry of ESD. We included all superficial esophageal lesions removed by ESD in 17 hospitals (20 endoscopists) between January 2016 and December 2021. Subepithelial lesions were excluded. The primary outcome was curative resection. We conducted a survival analysis and used logistic regression analysis to assess predictors of non-curative resection. Results A total of 102 ESD were performed on 96 patients. The technical success rate was 100% and the percentage of en-bloc resection was 98%. The percentage of R0 and curative resection was 77.5% (n = 79; 95% CI: 68%-84%) and 63.7% (n = 65; 95% CI: 54%-72%), respectively. The most frequent histology was Barrett-related neoplasia (n = 55 [53.9%]). The main reason for non-curative resection was deep submucosal invasion (n = 25). The centers with a lower volume of ESD obtained worse results in terms of curative resection. The rate of perforation, delayed bleeding and post-procedural stenosis were 5%, 5% and 15.7%, respectively. No patient died or required surgery due to an adverse effect. After a median follow-up of 14 months, 20 patients (20.8%) underwent surgery and/or chemoradiotherapy, and 9 patients died (mortality 9.4%). Conclusions In Spain, esophageal ESD is curative in approximately two out of three patients, with an acceptable risk of adverse events (AU)

Western outcomes of circumferential endoscopic submucosal dissection for early esophageal squamous cell carcinoma.

BACKGROUND AND AIMS: Circumferential endoscopic submucosal dissection (cESD) in the esophagus has been reported to be feasible in small Eastern case series. We assessed the outcomes of cESD in the treatment of early esophageal squamous cell carcinoma (ESCC) in Western countries. METHODS: We conducted an international study at 25 referral centers in Europe and Australia using prospective databases. We included all patients with ESCC treated with cESD before November 2022. Our main outcomes were curative resection according to European guidelines and adverse events. RESULTS: A total of 171 cESDs were performed on 165 patients. En bloc and R0 resections rates were 98.2% (95% confidence interval [CI], 95.0-99.4) and 69.6% (95% CI, 62.3-76.0), respectively. Curative resection was achieved in 49.1% (95% CI, 41.7-56.6) of the lesions. The most common reason for noncurative resection was deep submucosal invasion (21.6%). The risk of stricture requiring 6 or more dilations or additional techniques (incisional therapy/stent) was high (71%), despite the use of prophylactic measures in 93% of the procedures. The rates of intraprocedural perforation, delayed bleeding, and adverse cardiorespiratory events were 4.1%, 0.6%, and 4.7%, respectively. Two patients died (1.2%) of a cESD-related adverse event. Overall and disease-free survival rates at 2 years were 91% and 79%. CONCLUSIONS: In Western referral centers, cESD for ESCC is curative in approximately half of the lesions. It can be considered a feasible treatment in selected patients. Our results suggest the need to improve patient selection and to develop more effective therapies to prevent esophageal strictures.

Implementation of esophageal endoscopic submucosal dissection in Spain: Results from the nationwide registry. / Implementación de la disección endoscópica submucosa esofágica en España: resultados del registro nacional.

INTRODUCTION AND AIMS: The outcomes of endoscopic submucosal dissection (ESD) in the esophagus have not been assessed in our country. Our primary aim was to analyze the effectiveness and safety of the technique. MATERIAL AND METHODS: Analysis of the prospectively maintained national registry of ESD. We included all superficial esophageal lesions removed by ESD in 17 hospitals (20 endoscopists) between January 2016 and December 2021. Subepithelial lesions were excluded. The primary outcome was curative resection. We conducted a survival analysis and used logistic regression analysis to assess predictors of non-curative resection. RESULTS: A total of 102 ESD were performed on 96 patients. The technical success rate was 100% and the percentage of en-bloc resection was 98%. The percentage of R0 and curative resection was 77.5% (n=79; 95%CI: 68%-84%) and 63.7% (n=65; 95%CI: 54%-72%), respectively. The most frequent histology was Barrett-related neoplasia (n=55 [53.9%]). The main reason for non-curative resection was deep submucosal invasion (n=25). The centers with a lower volume of ESD obtained worse results in terms of curative resection. The rate of perforation, delayed bleeding and post-procedural stenosis were 5%, 5% and 15.7%, respectively. No patient died or required surgery due to an adverse effect. After a median follow-up of 14months, 20patients (20.8%) underwent surgery and/or chemoradiotherapy, and 9 patients died (mortality 9.4%). CONCLUSIONS: In Spain, esophageal ESD is curative in approximately two out of three patients, with an acceptable risk of adverse events.

The c.386A>C p.(Asn129Thr) variant in SMAD4 is likely to be pathogenic, causing Juvenile Polyposis Syndrome. A case report of a mosaic variant.

BACKGROUND: Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple hamartomatous gastrointestinal polyps. Here, we present a case of JPS with a mosaic variant in SMAD4. METHODS: Exome sequencing TRIO analysis, using germline DNA from the biological mother and father along with the index case (IC). RESULTS: A 46-year-old male with no family history of cancer presented with chronic iron deficiency anemia and was diagnosed with massive gastric polyposis (≥100 polyps). At the age of 59, he underwent a total gastrectomy, revealing numerous polyps occupying the entire gastric mucosa, including a 5 cm gastric hyperplastic polyp with high-grade dysplasia and focal adenocarcinoma. TRIO analysis identified the c.386A>C p.(Asn129Thr) variant in the SMAD4 gene at an allele frequency (AF) of 22%, suggesting its mosaic origin. Subsequently, the variant was found in heterozygosity in the IC's son, who exhibited two subcentimeter polyps in the colon and seven inflammatory gastric polyps with gastric inflammatory areas and hyperplasia, suggesting that the c.386A>C p.(Asn129Thr) variant in SMAD4 segregated with the phenotype. CONCLUSION: Our study provides evidence supporting the classification of the c.386A>C p.(Asn129Thr) variant in SMAD4 as a likely pathogenic variant. This finding contributes to improved accuracy in the diagnosis and genetic counseling of JPS.

Screening uptake of colonoscopy versus fecal immunochemical testing in first-degree relatives of patients with non-syndromic colorectal cancer: A multicenter, open-label, parallel-group, randomized trial (ParCoFit study).

BACKGROUND: Colonoscopy screening is underused by first-degree relatives (FDRs) of patients with non-syndromic colorectal cancer (CRC) with screening completion rates below 50%. Studies conducted in FDR referred for screening suggest that fecal immunochemical testing (FIT) was not inferior to colonoscopy in terms of diagnostic yield and tumor staging, but screening uptake of FIT has not yet been tested in this population. In this study, we investigated whether the uptake of FIT screening is superior to the uptake of colonoscopy screening in the familial-risk population, with an equivalent effect on CRC detection. METHODS AND FINDINGS: This open-label, parallel-group, randomized trial was conducted in 12 Spanish centers between February 2016 and December 2021. Eligible individuals included asymptomatic FDR of index cases <60 years, siblings or ≥2 FDR with CRC. The primary outcome was to compare screening uptake between colonoscopy and FIT. The secondary outcome was to determine the efficacy of each strategy to detect advanced colorectal neoplasia (adenoma or serrated polyps ≥10 mm, polyps with tubulovillous architecture, high-grade dysplasia, and/or CRC). Screening-naïve FDR were randomized (1:1) to one-time colonoscopy versus annual FIT during 3 consecutive years followed by a work-up colonoscopy in the case of a positive test. Randomization was performed before signing the informed consent using computer-generated allocation algorithm based on stratified block randomization. Multivariable regression analysis was performed by intention-to-screen. On December 31, 2019, when 81% of the estimated sample size was reached, the trial was terminated prematurely after an interim analysis for futility. Study outcomes were further analyzed through 2-year follow-up. The main limitation of this study was the impossibility of collecting information on eligible individuals who declined to participate. A total of 1,790 FDR of 460 index cases were evaluated for inclusion, of whom 870 were assigned to undergo one-time colonoscopy (n = 431) or FIT (n = 439). Of them, 383 (44.0%) attended the appointment and signed the informed consent: 147/431 (34.1%) FDR received colonoscopy-based screening and 158/439 (35.9%) underwent FIT-based screening (odds ratio [OR] 1.08; 95% confidence intervals [CI] [0.82, 1.44], p = 0.564). The detection rate of advanced colorectal neoplasia was significantly higher in the colonoscopy group than in the FIT group (OR 3.64, 95% CI [1.55, 8.53], p = 0.003). Study outcomes did not change throughout follow-up. CONCLUSIONS: In this study, compared to colonoscopy, FIT screening did not improve screening uptake by individuals at high risk of CRC, resulting in less detection of advanced colorectal neoplasia. Further studies are needed to assess how screening uptake could be improved in this high-risk group, including by inclusion in population-based screening programs. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02567045).

Development of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor-associated MUC1 antigen.

The overexpression of aberrantly glycosylated tumor-associated mucin-1 (TA-MUC1) in human cancers makes it a major target for the development of anticancer vaccines derived from synthetic MUC1-(glyco)peptide antigens. However, glycopeptide-based subunit vaccines are weakly immunogenic, requiring adjuvants and/or additional immunopotentiating approaches to generate optimal immune responses. Among these strategies, unimolecular self-adjuvanting vaccine constructs that do not need coadministration of adjuvants or conjugation to carrier proteins emerge as a promising but still underexploited approach. Herein, we report the design, synthesis, immune-evaluation in mice, and NMR studies of new, self-adjuvanting and self-assembling vaccines based on our QS-21-derived minimal adjuvant platform covalently linked to TA-MUC1-(glyco)peptide antigens and a peptide helper T-cell epitope. We have developed a modular, chemoselective strategy that harnesses two distal attachment points on the saponin adjuvant to conjugate the respective components in unprotected form and high yields via orthogonal ligations. In mice, only tri-component candidates but not unconjugated or di-component combinations induced significant TA-MUC1-specific IgG antibodies able to recognize the TA-MUC1 on cancer cells. NMR studies revealed the formation of self-assembled aggregates, in which the more hydrophilic TA-MUC1 moiety gets exposed to the solvent, favoring B-cell recognition. While dilution of the di-component saponin-(Tn)MUC1 constructs resulted in partial aggregate disruption, this was not observed for the more stably-organized tri-component candidates. This higher structural stability in solution correlates with their increased immunogenicity and suggests a longer half-life of the construct in physiological media, which together with the enhanced antigen multivalent presentation enabled by the particulate self-assembly, points to this self-adjuvanting tri-component vaccine as a promising synthetic candidate for further development.

TYPE II ACHALASIA WITH SUBSEQUENT RECOVERY OF ESOPHAGEAL MOTILITY - POEM.

CASE REPORT: 54-year-old woman with acromegaly due to pituitary macroadenoma that consulted for dysphagia for solids. In gastroscopy, it is observed difficulty in passing in the esophagogastric junction (EGJ). Under the suspect of Achalasia, a high-resolution esophageal manometry (HRM) was performed, observing a complete absence of motility of the esophageal body, panesophageal pressurization in > 20% of swallows and IRP of 21mmHg, confirming the diagnosis of type II Achalasia. Peroral endoscopic myotomy (POEM) is performed. After the intervention, the patient presented clinical improvement. In the control HRM carried out one year after the POEM, in addition to a decrease in IRP, is remarkable a partial recovery of motility in the upper and middle third of the esophagus. DISCUSSION: Achalasia is an esophageal motor disorder characterized by incomplete relaxation of the lower esophageal sphincter and a complete absence of peristalsis in the esophageal body. The cause of the absence of motility is the loss of the inhibitory neurons of the myenteric plexus, but the accurate etiopathogenesis is still unknown. Therefore, there is no curative treatment and all therapeutic options are symptomatic, aimed to relieve the obstruction of the EGJ. POEM is the newest method. Absence of motility of the esophageal body in patients with achalasia was believed to be irreversible. Nevertheless, more and more studies describe a partial recovery of motility observed in manometry after POEM, especially in type II Achalasia. The exact pathophysiological mechanism of this recovery is still unknown. IMAGES DESCRIPTION: Figure 1 (Before POEM): High-resolution manometry with a diagnosis of type II Achalasia: Absence of motility, panesophageal pressurization and IRP 21mmHg Figure 2 (After POEM): High resolution manometry showing ineffective esophageal motility (partial recovery of motility) after POEM with IRP of 4mmHg.

Underwater versus conventional EMR of large nonpedunculated colorectal lesions: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: Underwater EMR (UEMR) is an alternative procedure to conventional EMR (CEMR) to treat large, nonpedunculated colorectal lesions (LNPCLs). In this multicenter, randomized controlled clinical trial, we aimed to compare the efficacy and safety of UEMR versus CEMR on LNPCLs. METHODS: We conducted a multicenter, randomized controlled clinical trial from February 2018 to February 2020 in 11 hospitals in Spain. A total of 298 patients (311 lesions) were randomized to the UEMR (n = 149) and CEMR (n = 162) groups. The main outcome was the lesion recurrence rate in at least 1 follow-up colonoscopy. Secondary outcomes included technical aspects, en bloc resection rate, R0 resection rates, and adverse events, among others. RESULTS: There were no differences in the overall recurrence rate (9.5% UEMR vs 11.7% CEMR; absolute risk difference, -2.2%; 95% CI, -9.4 to 4.9). However, considering polyp sizes between 20 and 30 mm, the recurrence rate was lower for UEMR (3.4% UEMR vs 13.1% CEMR; absolute risk difference, -9.7%; 95% CI, -19.4 to 0). The R0 resection showed the same tendency, with significant differences favoring UEMR only for polyps between 20 and 30 mm. Overall, UEMR was faster and easier to perform than CEMR. Importantly, the techniques were equally safe. CONCLUSIONS: UEMR is a valid alternative to CEMR for treating LNPCLs and could be considered the first option of treatment for lesions between 20 and 30 mm due to its higher en bloc and R0 resection rates. (Clinical trial registration number: NCT03567746.).

Novel Oxime-Derivatized Synthetic Triterpene Glycosides as Potent Saponin Vaccine Adjuvants.

Vaccine adjuvants are key for optimal vaccine efficacy, increasing the immunogenicity of the antigen and potentiating the immune response. Saponin adjuvants such as the carbohydrate-based QS-21 natural product are among the most promising candidates in vaccine formulations, but suffer from inherent drawbacks that have hampered their use and approval as stand-alone adjuvants. Despite the recent development of synthetic derivatives with improved properties, their full potential has not yet been reached, allowing the prospect of discovering further optimized saponin variants with higher potency. Herein, we have designed, chemically synthesized, and immunologically evaluated novel oxime-derivatized saponin adjuvants with targeted structural modifications at key triterpene functionalities. The resulting analogues have revealed important findings into saponin structure-activity relationships, including adjuvant mechanistic insights, and have shown superior adjuvant activity in terms of significantly increased antibody response augmentation compared to our previous saponin leads. These newly identified saponin oximes emerge as highly promising synthetic adjuvants for further preclinical development towards potential next generation immunotherapeutics for future vaccine applications.

Clinical outcome of non-curative endoscopic submucosal dissection for early colorectal cancer.

OBJECTIVE: Endoscopic submucosal dissection (ESD) in a curative intent for submucosa-invasive early (T1) colorectal cancers (T1-CRCs) often leads to subsequent surgical resection in case of histologic parameters indicating higher risk of nodal involvement. In some cases, however, the expected benefit may be offset by the surgical risks, suggesting a more conservative approach. DESIGN: Retrospective analysis of consecutive patients with T1-CRC who underwent ESD at 13 centres ending inclusion in 2019 (n=3373). Cases with high risk of nodal involvement (non-curative ESD: G3, submucosal invasion>1000 µm, lymphovascular involvement, budding or incomplete resection/R1) were analysed if follow-up data (endoscopy/imaging) were available, regardless of the postendoscopic management (follow-up vs surgery) selected by the multidisciplinary teams in these institutions. Comorbidities were classified according to Charlson Comorbidity Index (CCI). Outcomes were disease recurrence, death and disease-related death rates in the two groups. Rate of residual disease (RD) at both the previous resection site and regional lymph nodes was assessed in the surgical cases as well as from follow-up in the follow-up group. RESULTS: Of 604 patients treated by colorectal ESD for submucosally invasive cancer, 207 non-curative resections (34.3%) were included (138 male; mean age 67.6±10.9 years); in 65.2% of cases, no complete resection was achieved (R1). Of the 207 cases, 60.9% (n=126; median CCI: 3; IQR: 2-4) underwent surgical treatment with RD in 19.8% (25/126), while 39.1% (n=81, median CCI: 5; IQR: 4-6) were followed up by endoscopy in all cases. Patients in the follow-up group had a higher overall mortality (HR=3.95) due to non-CRC causes (n=9, mean survival after ESD 23.7±13.7 months). During this follow-up time, tumour recurrence and disease-specific survival rates were not different between the groups (median follow-up 30 months; range: 6-105). CONCLUSION: Following ESD for a lesion at high risk of RD, follow-up only may be a reasonable choice in patients at high risk for surgery. Also, endoscopic resection quality should be improved. TRIAL REGISTRATION NUMBER: NCT03987828.

Chemical biology tools to interrogate the roles of O-GlcNAc in immunity.

The O-linked ß-N-acetylglucosamine (O-GlcNAc) glycosylation of proteins is an essential and dynamic post-translational modification in mammalian cells that is regulated by the action of two enzymes. O-GlcNAc transferase (OGT) incorporates this monosaccharide on serine/threonine residues, whereas O-GlcNAcase (OGA) removes it. This modification is found on thousands of intracellular proteins involved in vital cellular processes, both under physiological and pathological conditions. Aberrant expression of O-GlcNAc has been implicated in diseases such as Alzheimer, diabetes, and cancer, and growing evidence over the last decade has also revealed key implications of O-GlcNAcylation in immunity. While some key signaling pathways involving O-GlcNAcylation in immune cells have been discovered, a complete mechanistic understanding of how O-GlcNAcylated proteins function in the immune system remains elusive, partly because of the difficulties in mapping and quantifying O-GlcNAc sites. In this minireview, we discuss recent progress on chemical biology tools and approaches to investigate the role of O-GlcNAcylation in immune cells, with the intention of encouraging further research and developments in chemical glycoimmunology that can advance our understanding of O-GlcNAc in immunity.

Location, morphology and invasiveness of lateral spreading tumors in the colorectum differ between two large cohorts from an eastern and western country.

BACKGROUND AND STUDY AIMS: Data from Japanese series show that surface morphology of laterally spreading tumors (LST) in the colon identifies lesions with different incidence and pattern of submucosal invasion. Such data from western countries are scarce. We compared clinical and histological features of LST in a western country and an eastern country, with special interest on mucosal invasiveness of LST, and investigated the effect of clinical factors on invasiveness in both countries. PATIENTS AND METHODS: Patients with LST lesions ≥20mm were included from a multicenter prospective registry in Spain and from a retrospective registry from the National Cancer Center Hospital East, Japan. The primary outcome was the presence of submucosal invasion in LST. The secondary outcome was the presence of high-risk histology, defined as high-grade dysplasia or submucosal invasion. RESULTS: We evaluated 1102 patients in Spain and 663 in Japan. Morphological and histological characteristics differed. The prevalence of submucosal invasion in Japan was six-fold the prevalence in Spain (Prevalence Ratio PR=5.66; 95%CI: 3.96, 8.08), and the prevalence of high-risk histology was 1.5 higher (PR=1.44; 95%CI: 1.31, 1.58). Compared to the granular homogeneous type and adjusted by clinical features, granular mixed, flat elevated, and pseudo-depressed types were associated with higher odds of submucosal invasion in Japan, whereas only the pseudo-depressed type showed higher risk in Spain. Regarding high-risk histology, both granular mixed and pseudo-depressed were associated with higher odds in Japan, compared with only the granular mixed type in Spain. CONCLUSION: This study reveals differences in location, morphology and invasiveness of LST in an eastern and a western cohort.

Endoscopy-Related Bleeding and Thromboembolic Events in Patients on Direct Oral Anticoagulants or Vitamin K Antagonists.

BACKGROUND & AIMS: Few prospective studies have assessed the safety of direct oral anticoagulants (DOACs) in elective endoscopy. Our primary aim was to compare the risks of endoscopy-related gastrointestinal bleeding and thromboembolic events in patients on DOACs or vitamin K antagonists (VKAs) in this setting. Secondarily, we examined the impact of the timing of anticoagulant resumption on the risk of delayed bleeding in high-risk therapeutic procedures. METHODS: We conducted a multicenter, prospective, observational study from January 2018 to March 2020 of 1602 patients on oral anticoagulants (1004 on VKAs and 598 on DOACs) undergoing 1874 elective endoscopic procedures. Our primary outcomes were 90-day thromboembolic events and 30-day endoscopy-related gastrointestinal bleeding. The inverse probability of treatment weighting propensity score method was used for baseline covariate adjustment. RESULTS: The 2 groups had similar risks of endoscopy-related gastrointestinal bleeding (VKAs vs DOACs, 6.2% vs 6.7%; adjusted odds ratio [OR], 1.05; 95% CI, 0.67-1.65) and thromboembolic events (VKAs vs DOACs, 1.3% vs 1.5%; adjusted OR, 0.90; 95% CI, 0.34-2.38). In high bleeding risk procedures (n = 747), delayed anticoagulant resumption (> 48 hours or 24-48 hours vs < 24 hours) did not reduce the risk of postprocedural bleeding (10.3%, 9%, and 5.8%, respectively; adjusted P = .43). Hot and cold snare polypectomy were the most frequent high-risk interventions (41.8% and 39.8%, respectively). CONCLUSION: In a prospective study of patients on DOACs or VKAs undergoing elective endoscopy, endoscopy-related bleeding and thromboembolic events showed similar risk. Our study suggests that early anticoagulant resumption is safe in most patients, but more data are needed for advanced high-risk therapeutic procedures.

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.

Design, synthesis, and initial immunological evaluation of glycoconjugates based on saponin adjuvants and the Tn antigen.

We report the first synthesis and immunological evaluation of a new glycoconjugate design based on streamlined saponin adjuvants and the Tn carbohydrate antigen. While the novel synthetic constructs induced moderate antibody responses in mice, the versatile chemical platform is amenable to further structure-activity optimizations for the development of self-adjuvanting glycoconjugate cancer vaccines.

Advances in chemical probing of protein O-GlcNAc glycosylation: structural role and molecular mechanisms.

The addition of O-linked-ß-D-N-acetylglucosamine (O-GlcNAc) onto serine and threonine residues of nuclear and cytoplasmic proteins is an abundant, unique post-translational modification governing important biological processes. O-GlcNAc dysregulation underlies several metabolic disorders leading to human diseases, including cancer, neurodegeneration and diabetes. This review provides an extensive summary of the recent progress in probing O-GlcNAcylation using mainly chemical methods, with a special focus on discussing mechanistic insights and the structural role of O-GlcNAc at the molecular level. We highlight key aspects of the O-GlcNAc enzymes, including development of OGT and OGA small-molecule inhibitors, and describe a variety of chemoenzymatic and chemical biology approaches for the study of O-GlcNAcylation. Special emphasis is placed on the power of chemistry in the form of synthetic glycopeptide and glycoprotein tools for investigating the site-specific functional consequences of the modification. Finally, we discuss in detail the conformational effects of O-GlcNAc glycosylation on protein structure and stability, relevant O-GlcNAc-mediated protein interactions and its molecular recognition features by biological receptors. Future research in this field will provide novel, more effective chemical strategies and probes for the molecular interrogation of O-GlcNAcylation, elucidating new mechanisms and functional roles of O-GlcNAc with potential therapeutic applications in human health.

Implementation of endoscopic submucosal dissection in a country with a low incidence of gastric cancer: Results from a prospective national registry.

INTRODUCTION: Endoscopic submucosal dissection (ESD) has become the treatment of choice for early gastric malignancies. In recent years, the ESD technique has been implemented in Western countries with increasing use. OBJECTIVES: To describe the results of gastric ESD in a Western country with a low incidence of gastric cancer. PATIENTS AND METHODS: The prospective national registry was conducted over 4 years in 23 hospitals, including 30 endoscopists. Epithelial and subepithelial lesions (SEL) qualified to complete removal with ESD were assessed. The technique, instruments, and solution for submucosal injection varied at the endoscopist's discretion. ESD was defined as difficult when: en-bloc resection was not achieved, had to be converted to a hybrid resection, lasted more than 2 h or an intraprocedural perforation occurred. Additionally, independent risk factors for difficult ESD were analyzed. RESULTS: Two hundred and thirty gastric ESD in 225 patients were performed from January 2016 to December 2019 (196 epithelial and 34 SEL). Most lesions were located in the lower stomach (111; 48.3%). One hundred and twenty-eight (55.6%) ESD were considered difficult. The median procedure time was 105 min (interquartile range [IQR]: 60-150). The procedure time for SEL was shorter than for epithelial lesions (90 min [45-121] vs. 110 min [62-160]; p = 0.038). En-bloc, R0, and curative resection rates were 91.3%, 75.2%, and 70.9%, respectively. Difficult ESD had lower R0 resection rates than ESD that did not meet the difficulty criteria (64.8% and 87.6%; p = 0.000, respectively). Fibrosis and poor maneuverability were independent factors associated with difficult ESD (OR 3.6, 95%CI 1.1-11.74 and OR 5.07, 95%CI 1.6-16.08; respectively). CONCLUSIONS: Although the number of cases is limited, the results of this analysis show acceptable en-bloc and R0 rates in gastric ESD considering the wide variability in experience among the operators. Fibrosis and poor maneuverability were associated with more difficulty in completing ESD.