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Background: Endoscopic Submucosal Dissection (ESD) has become the standard therapy for early malignant lesions in the gastrointestinal tract and has shown as good oncological surgery results. Approximately 30% of ESDs do not meet the criteria for oncological curability, and upfront surgery is indicated. Hence, about 40% of patients with an indication for surgery are advised against surgery because of comorbidities and an advanced age. Methods: We performed a multicenter retrospective cohort study on the long-term outcomes of non-curative ESDs, performed between 2009 and May 2024, without additional tumor therapy. The primary outcome was the recurrence of malignancy, either local malignancy or lymph node metastasis during follow-up, or death. We compared the outcomes between two cohorts: after non-curative ESD (ncESD) and after curative ESD (cESD). Results: A total of 374 ESDs were analyzed in this study. Overall, the technical success rate was 91%, and the oncological curative resection criteria were met in 70.9% of patients. Severe complications occurred in 5% of cases without procedure-associated mortality. In the ncESD group, 20% (7/35) of patients had a recurrence of malignancy primarily due to positive horizontal margins in the resection specimens, and 3 out of 35 died due to a non-oncological reason during the follow-up (mean length 36.6 months). In the cESD group, 3% (1/33) of patients had tumor recurrence, and 1 patient died because of a non-oncological reason. The tumor recurrence rate between the cohorts was significant (p = 0.017), and overall mortality did not show significance (p = 0.33). Conclusions: Especially in the elderly and multimorbid patients, the recommendation to perform rescue surgery after non-curative ESD remains challenging. Residual malignancy rates in surgical resection specimens are low, recurrence rates of malignancy are low, and mortality rates for non-oncological reasons are high in this population. There is a need for more data for the individualization of patient management after non-curative ESD. [ABSTRACT FROM AUTHOR]

(1) Background: Vulnerable populations including transplant recipients are jeopardised by COVID-19. Herein, we report on B and T cell responses among liver and kidney organ recipients at our centre. (2) Methods: 23 liver and 45 kidney (14 thereof combined kidney/pancreas) transplanted patients were vaccinated with two doses of BNT162b2 followed by a booster dose of mRNA-1273 in 28 non-responders 4 months thereafter. Anti-SARS-CoV-2-Ig was measured by specific ELISA and virus neutralisation assay; T cell responses were measured by a spike protein-specific IFN-γ release assay. (3) Results: Compared to controls, B and T cell responses were weak in transplant recipients, particularly in those without prior exposure to SARS-CoV-2. Within this group, only 15% after the first and 58.3% after the second vaccination achieved seroconversion. A total of 14 out of 28 vaccination non-responders achieved a seroconversion after a third dose. Vaccination side effects were more frequent in healthy controls. The use of mycophenolate was associated with reduced anti-SARS-CoV-2-Ig production. (4) Conclusions: Our data confirm that vaccination responses are insufficient after standard vaccination in liver and kidney transplant recipients and are affected to a variable degree by specific immunosuppressants, particularly mycophenolate. Monitoring vaccination success and re-vaccinating those who are unresponsive seems prudent to achieve sufficient titres. Overall, prospective large-scale, multinational, multicentre studies or high-quality meta-analyses will be needed to generate personalised vaccination strategies in order to achieve protective immunity in high-risk, hard-to-immunize populations. [ABSTRACT FROM AUTHOR]

Introduction Over the past few years, the prevalence of obesity and type 2 diabetes (T2D) has risen dramatically throughout the world. One of the hallmarks of these disease entities has [...], The innate immune system and its major mediators, i.e., cytokines, are increasingly recognized as being of crucial importance in metabolic inflammation as observed in morbid obesity and type 2 diabetes (T2D). Morbid obesity is commonly associated with adipose tissue inflammation. Adipose tissue inflammation is characterized by an increased expression of various pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 and -6, and by a rather heterogenous cellular infiltrate including monocytes/macrophages, neutrophils, B lymphocytes, T lymphocytes, and others. It has been demonstrated that in patients with severe obesity and fatty liver disease, expression of these pro-inflammatory cytokines in adipose tissue is 100-1000 times higher compared with that in the liver. Therefore, the adipose tissue can be considered in the state of severe obesity as the 'cytokine factory' of the body. Rapid weight loss almost entirely eliminates pro-inflammatory cytokines in the adipose tissue, and therefore provides a very potent anti-inflammatory strategy. In conclusion, there is increasing evidence that peripheral tissues such as the adipose tissue may affect disease processes in target organs such as the liver, pancreas, heart, or blood vessels, and may therefore significantly contribute to chronic inflammation as observed in obesity and T2D. Key words: inflammation, non-alcoholic fatty liver disease, metabolism, adipocytokines, insulin resistance, adipose tissue inflammation. On reconnait de plus en plus l'importance cruciale du systeme immunitaire inne et de ses mediateurs principaux, i.e., les cytokines, dans l'inflammation metabolique observee dans l'obesite morbide et le diabete de type 2 (DT2). L'obesite morbide est generalement associee a une inflammation du tissu adipeux. L'inflammation du tissu adipeux se caracterise par une expression accrue de differentes cytokines pro-inflammatoires telles le facteur necrosant des tumeurs a, l'interleukine-1 et l'interleukine-6, ainsi que par une infiltration cellulaire assez heterogene comportant des monocytes/macrophages, neutrophiles, lymphocytes B, lymphocytes T et autres. Il a ete demontre chez des patients presentant une obesite severe et une maladie dite du foie gras, que l'expression de ces cytokines pro-inflammatoires dans le tissu adipeux est de 100 a 1000 fois plus elevee comparativement a leur expression dans le foie. Ainsi, le tissu adipeux peut etre considere dans les situations d'obesite severe comme la << manufacture de cytokines >> du corps. Une perte de poids rapide elimine presqu'entierement les cytokines proinflammatoires du tissu adipeux et constitue ainsi une strategie anti-inflammatoire tres efficace. En conclusion, il existe de plus en plus de preuves que les tissus peripheriques comme le tissu adipeux peuvent affecter les processus pathologiques dans les organes cibles comme le foie, le pancreas, le coeur ou les vaisseaux, et qu'ils peuvent ainsi contribuer de maniere significative a l'inflammation chronique telle qu'observee dans l'obesite et de DT2. [Traduit par la Redaction] Mots-cles: inflammation, maladie du foie gras non alcoolique, adipocytokines, resistance a l'insuline, inflammation du tissu adipeux.

RANKL (also known as TNFSF11) is a member of the tumor necrosis factor superfamily and, after ligation with its cognate receptor RANK (also known as TNFRSF11a), is a potent stimulator [...], Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver (1-3). There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and b-cell dysfunction, although the molecular mechanisms involved are incompletely understood (3-6). We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P < 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.