COVID-19 Vaccination in Inflammatory Bowel Disease (IBD)

Vaccines against SARS-CoV-2 are believed to play a key role in the suppression of the COVID-19 pandemic. However, patients suffering from inflammatory bowel diseases (IBD) were excluded from SARS-CoV-2 vaccines trials. Therefore, concerns regarding vaccination efficacy and safety among those patients were raised. Overall, vaccination is well tolerated in the IBD population, and different gastroenterological societies recommend vaccinating patients with IBD at the earliest opportunity to do so. Nevertheless, very little is known about the safety of COVID-19 vaccines in special IBD populations such as pregnant and breastfeeding women or pediatric patients, and further research on this matter is crucial. The available data on vaccine efficacy are promising and show high seroconversion rates in IBD patients on different immune-modifying therapies. However, patients treated with high doses of systemic corticosteroids, infliximab or infliximab and immunomodulators may have a blunted response to the vaccination. The data on COVID-19 vaccination willingness among patients with IBD are conflicting. Nevertheless, vaccine effectiveness and safety are reported to be the most common reasons for hesitancy. This review examines the effectiveness and safety of COVID-19 vaccines and describes vaccination willingness and the reasons for potential hesitancy among patients with IBD

Efficacy, Safety and Future Perspectives of JAK Inhibitors in the IBD Treatment

Although development of biologics has importantly improved the effectiveness in inducing and maintaining remission in inflammatory bowel disease (IBD), biologic therapies still have several limitations. Effective, low-cost drug therapy with good safety profile and compliance is therefore a substantial unmet medical need. A promising target for IBD treatment strategies are Janus kinase (JAK) inhibitors, which are small molecules that interact with cytokines implicated in pathogenesis of IBD. In contrast to monoclonal antibodies, which are able to block a single cytokine, JAK inhibitors have the potential to affect multiple cytokine-dependent immune pathways, which may improve the therapeutic response in some IBD patients. Tofacitinib, inhibiting signaling via different types of JAKs, has been already approved for ulcerative colitis, and several other small-molecule are still under investigation. However, one of the main concerns about using JAK inhibitors is the risk of thromboembolic events. Moreover, patients with COVID-19 appear to have an increased susceptibility for immunothrombosis. Therefore, thrombotic complications may become a serious limitation in the use of JAK inhibitors in the SARS-CoV-2 pandemic. As many questions about safety and efficacy of small molecules still remain unclear, in our review we present the current data regarding approved JAK inhibitors, as well as those in clinical development for the treatment of IBD

Genetically determined telomere length is associated with pancreatic neuroendocrine neoplasms onset

: Introduction Telomere length (TL) is a potential indicator of cancer predisposition, however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet. Methods A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100 and ZBTB46-rs755017) and 291 PanNEN cases and 1686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN. Results An association between genetically determined long telomeres and the risk of developing PanNEN (OR=1.99; CI 1.33-2.98; P=0.0008), for highest vs median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C_vs_G/G=2.27, CI 1.58-3.27, P=8.80×10-6) and TERT-rs2736100 (ORC/A_vs_C/C=2.03, CI 1.42-2.91, P=1.06×10-4). Conclusion In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN

Dissecting the genetic heterogeneity of gastric cancer

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709</p