BackgroundColorectal cancer (CRC) is among the most prevalent malignancies worldwide and remains the second leading cause of cancer-related death. Curative treatment approaches rely on R0 resection with adequate regional lymphadenectomy. Current international guidelines recommend a lymph node yield (LNY) of at least 12 lymph nodes to ensure accurate pathological staging and to guide decisions regarding adjuvant therapy. However, it remains controversial whether this historically established threshold is sufficient to optimize oncological outcomes. The aim of this study was to evaluate the association between operative LNY and clinicopathological characteristics, disease-free survival (DFS), and overall survival (OS) in patients undergoing curative resection for CRC.MethodsThis retrospective study included 333 patients who underwent colorectal cancer resection at a high-volume center in Germany between 2016 and 2023. Only patients with Union for International Cancer Control (UICC) stage I–III disease who underwent curative-intent R0 resection were included. Patients were stratified into two groups according to LNY: <20 versus ≥20 retrieved lymph nodes.ResultsLNY of ≥20 was associated with distinct tumor- and treatment-related characteristics, including advanced local tumor stage, microsatellite instability (MSI), colon cancer, right hemicolectomy, and absence of neoadjuvant treatment. No significant differences were observed between the groups regarding nodal stage, number of positive lymph nodes, lymphatic invasion, surgical approach, urgency of surgery, intraoperative blood loss, major postoperative morbidity, anastomotic leakage, chyle leak, reoperation or length of hospital stay. Higher LNY was not independently associated with improved OS or DFS in the overall cohort. Subgroup analyses stratified by UICC stage showed no significant association between LNY ≥20 on OS or DFS in stage I, II, or III disease. In procedure-specific analyses, LNY ≥20 was associated with improved OS after anterior rectal resection.ConclusionsOverall, these findings suggest that higher LNY is not a general prognostic determinant of oncological outcomes, but may have procedure-specific prognostic relevance.

Aberrant mucin-type O-glycosylation is a common feature of pancreatic ductal adenocarcinoma (PDAC), yet its functional contribution to pancreatic tumorigenesis remains incompletely defined. In particular, whether defective core 1 O-glycan maturation cooperates with oncogenic KRAS during early pancreatic neoplasia has not been fully resolved. Here, we addressed this question by deleting Cosmc (C1galt1c1), the obligate molecular chaperone for T-synthase (C1galt1), in a pancreas-specific Kras-driven mouse model. Analysis of human PDAC tissue microarrays revealed frequent expression of the truncated O-glycan epitopes Tn and sialyl-Tn, supporting the clinical relevance of impaired O-glycan elongation in pancreatic cancer. In vivo, pancreas-specific Cosmc loss in the setting of oncogenic Kras accelerated pancreatic tumor progression, enhanced tissue proliferation, altered acidic mucin-associated glycosylation, and promoted pronounced stromal remodeling. Lectin histochemistry and biochemical analyses confirmed robust accumulation of Tn antigen in Cosmc-deficient pancreatic tumors. To define molecular programs associated with this phenotype, we performed transcriptomic and proteomic profiling of tumor-derived PDAC cell lines together with VVA-enriched glycoproteomic analysis of pancreatic tissues and cell lines. These approaches identified coordinated remodeling of pathways linked to extracellular matrix organization, adhesion, cytoskeletal regulation, stress adaptation, and metabolic reprogramming. Together, these data identify Cosmc-dependent O-glycosylation as a regulator of Kras-driven pancreatic carcinogenesis. Our findings support a model in which truncated O-glycans contribute to PDAC progression in association with remodeling of the tumor glycoproteome and stromal architecture during Kras-driven pancreatic tumor evolution.

BACKGROUND/AIM:Colorectal cancer liver metastases (CRLM) remain a leading cause of cancer-related mortality. Although hepatic resection is the only established curative option, recurrence exceeds 60%, underscoring substantial biologic heterogeneity. Liver transplantation (LT) has re-emerged for highly selected patients with unresectable CRLM, but optimal biologic selection criteria remain undefined. This study integrates genomic and clinical data to develop a biologically grounded framework for surgical and transplant decision-making. MATERIALS AND METHODS:The Memorial Sloan Kettering 2017 metastatic colorectal cancer cohort was analyzed using cBioPortal-formatted clinical, genomic, and survival data. The study included patients with liver-only metastatic presentation. Genomic variables comprised KRAS, NRAS, BRAF, TP53, APC, PIK3CA, SMAD4 alterations, tumor mutational burden, microsatellite instability, and copy-number alteration burden. Survival was assessed using Kaplan-Meier and Cox models. A predefined molecular-risk classification stratified patients into low (RAS/RAF wild-type, SMAD4-intact), intermediate (isolated KRAS mutation), and high risk (NRAS, BRAF, or SMAD4 alterations). Machine-learning models predicted 24-month mortality. RESULTS:Among 503 patients, molecular-risk groups demonstrated distinct survival (5-year OS: 74.5%, 56.6%, and 49.8%; p<0.001). Intermediate- and high-risk groups were independently associated with worse survival (HR=1.71 and 2.60, respectively). Integrated clinicogenomic models modestly improved predictive performance (AUROC 0.697), with BRAF mutation, tumor sidedness, and age as key contributors. Inclusion of metastasectomy status increased AUROC but reflected post-treatment bias. CONCLUSION:Molecular-risk stratification and integrated modeling identify clinically meaningful prognostic groups in CRLM. These findings support incorporation of genomic profiling into precision surgical and transplant evaluation, while emphasizing the need for prospective validation.

Background Colorectal cancer remains among the most common malignancies worldwide and the second leading cause of cancer-related death. Prior studies suggest that socioeconomic deprivation is associated with higher incidence and poorer outcomes in colorectal cancer patients. Methods We conducted a retrospective study of 476 patients who underwent colorectal cancer resection at a high-volume center in Germany between 2016 and 2023. Area-level socioeconomic status (SES) was estimated using a region-specific purchasing power index (PPI) derived from patients' residential postal codes. We retrospectively examined whether SES was associated with mode of presentation, perioperative course, postoperative complications, and oncologic outcomes. In addition, a prespecified exploratory subgroup analysis was performed by comparing patients in the highest 20% (top) and lowest 20% (bottom) of the cohort according to PPI distribution. Results In the overall cohort, higher area-level SES was associated with emergency surgery. In the subgroup analysis, the top SES subgroup was also associated with older age and postoperative complications. We further observed significant associations between the bottom SES subgroup and both younger age at diagnosis and higher body mass index (BMI). No statistically significant association between SES and overall or disease-free survival was observed in our patient cohort. Conclusions In this single-center study, area-level SES was associated with distinct patient and perioperative profiles, but not with long-term oncologic outcomes. These findings suggest potentially actionable differences in risk profiles across SES strata, particularly regarding age at diagnosis, obesity, and complication burden.

BACKGROUND:Primary abdominal wall closure after intestinal and multivisceral transplants remains a challenge. Avascular transplant of the abdominal rectus fascia (TxARF) has emerged as an alternative to reduce postoperative morbidity and mortality. This study aimed to evaluate tissue and immunological responses to TxARF in a rat model without immunosuppression. METHODS:A total of 34 TxARFs were performed in rats (17 isogenic [ISO] and 17 allogeneic [ALLO]), with recipients sacrificed at 30 and 120 days after surgery. Serum and graft samples were analyzed for donor-specific antibodies (DSAs), elasticity, cellular analysis by flow cytometry, histopathology, and immunohistochemistry for CD3+ cells. RESULTS:Muscle fiber loss was observed at 30 days, with collagen content significantly higher in ALLO (55.97 ± 3.68) and ISO (33.13 ± 3.85) groups than controls (3.78 ± 0.47) (P <.0001). The lateral portions of the grafts showed more large blood vessels, whereas the medial areas had small vessels. The ALLO group exhibited increased resistance to stretching and elasticity loss. Despite the lack of immunosuppression, CD3+ levels in all groups were similar to controls, with only 1 animal showing a positive DSA response. CONCLUSION:Long-term changes include muscle fiber replacement with fibrosis and loss of elasticity, especially in the alloreactive group. No significant immune response occurred, confirming the fascia's low immunogenicity.

Introduction and Objectives: Immunotherapy with atezolizumab/bevacizumab (atezo/bev) is an established first-line treatment for patients with non-resectable hepatocellular carcinoma (HCC). Despite notable successes, only a subset of patients shows treatment response, highlighting the need for biomarkers to identify those likely to benefit from this therapy. Materials and Methods: In this biomarker study, 143 patients with atezo/bev-treated HCC were enrolled across three European centers. Baseline cytokine levels were measured using a flow cytometric multiplex bead assay. Overall survival (OS) analysis, reported as hazard ratios (HR), was conducted in an unbiased manner, with patients divided into a discovery cohort (one center, 63 patients) and a validation cohort (two centers, 80 patients). Results: Our cohorts show typical baseline characteristics of Western HCC patients, with alcohol-related liver disease (35.0 %) and hepatitis C (21.7 %) as the main HCC etiologies. Elevated serum IL-6 (cut-off 18.22 pg/ml) was associated with poor OS in both the discovery (HR 2.6, 95 % CI 1.2–5.6, p = 0.013) and validation cohorts (HR 2.4, 95 % CI 1.3–4.4, p = 0.005). Multivariate analysis confirmed elevated IL-6 to be a significant prognostic biomarker of poor OS (HR 2.1, 95 % CI 1.1–3.9, p = 0.021) after adjusting for established risk factors. Conclusions: We identify elevated serum IL-6 levels as prognostic biomarker in patients with advanced HCC in Western countries. Importantly, this association was independent of infection with viral hepatitis, thus extending the previously reported associations between IL-6 and treatment response in East Asian cohorts.

Altered O-glycosylation is a key contributor to various pathophysiological processes. Notably, the expression of the Tn antigen is primarily attributed to dysfunction of the chaperone Cosmc, while the overexpression of polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) has also been implicated in numerous diseases. We generated a transgenic mouse model with conditional Cosmc-knockout and simultaneous overexpression of polypeptide N-acetylgalactosaminyltransferase 2 (GalNT2) mediated by the pancreas-specific transcription factor 1a (Ptf1a)-Cre mouse strain to investigate the effect of Tn antigen overexpression on the pancreas in vivo. Histopathological examination of the transgenic pancreas revealed a chronic pancreatitis phenotype with interlobular fibrosis and focal necrosis after only a few weeks as a result of Tn antigen overexpression. In the later stages, there was a progressive loss of pancreatic parenchyma with consecutive exocrine pancreatic insufficiency and malnutrition in the transgenic mice. Flow cytometric analyses have also confirmed that significant infiltration of immune cells occurs in the course of pancreatitis. In the transgenic mouse model presented here, we demonstrated that overexpression of the Tn antigen in the pancreas results in chronic pancreatitis, highlighting the pathophysiological importance of truncated O-glycosylation.

In solid organ transplantation, chimerism inevitably occurs via the coexistence of donor-derived cells from the graft and host cells throughout the recipient. However, long-term immunosuppressive treatment is needed to suppress host immune responses to the foreign organ graft. The deliberate induction of stable mixed bone marrow chimerism to achieve donor-specific immunological tolerance in solid organ graft recipients is an ambitious goal that may significantly contribute to the long-term survival of solid organ grafts and their recipients. While this strategy has been effectively established in laboratory animals and some promising clinical case series have been reported, widespread clinical application is still limited by the toxicity of the necessary conditioning regimens. On the other hand, the naturally occurring chimeric state resulting from the bidirectional transplacental cell trafficking during pregnancy, the so-called feto-maternal microchimerism, can also induce immune tolerance and thus influence the outcome of mother-to-child or child-to-mother organ transplantation. This review provides an overview of the field's historical development, clinical results, and underlying principles of (micro) chimerism-based tolerance.

A strong sex-bias characterizes many respiratory immune diseases and has been attributed to sexually dimorphic immune responses. However, the role of lung-resident immunity in this context remains elusive. Here, we thoroughly characterized the lung-resident immune landscape in male and female mice, with a special focus on sex hormone effects in this context. Androgens were found to exert the strongest effects, markedly impacting B cells and neutrophils in both male and female lungs. Castrated males exhibited increased, while testosterone-treated females and males decreased lung-residing B cells. Testosterone supplementation of castrated males and females resulted in increased lung-residing neutrophils. Sex-mismatched orthotopic lung transplantation further supported these findings, since lungs isolated from female donors exhibited reduced tissue-residing B cells after their transplantation into male recipients. For the remaining lung-resident immune cell populations, sex differences were observed at the level of cell frequencies, with male lungs exhibiting higher frequencies of alveolar macrophages and lower frequencies of lung-resident dendritic cells and CD4⁺ tissue-resident memory T cells. Castration reversed some of these findings. Our findings highlight that the sexual dimorphism of the lung-resident immune landscape is modulated by sex hormones and especially androgens, thereby providing insights into the sex-specific manifestation of respiratory immune diseases.

Background He use of mouse liver transplantation models remains crucial for answering questions regarding organ transplantation, tissue-resident immunity and tumor biology. The learning curve for this complex procedure involves use of animals without creating scientific output. We present a recipient mouse and donor liver model with realistic vessels for training in mouse liver transplantation, designed to reduce the number of animals needed during the training. Methods A 3D-model of the liver, skeleton and vessels (vena cava, hepatic artery and portal vein) was created using computed tomography images of a real mouse and 3D-printing to simulate orthotopic liver transplantation. Microsurgical experts from multiple research groups evaluated this model for usability, procedural details, and on how well the materials mimicked the real tissue. Results We successfully created an artificial model featuring the mouse body, organs, and vessels needed for initial training in mouse liver transplantation. The evaluation found it to realistically mimic the confined space of the surgical site and determined that it could be used for vessel anastomoses with suturing and the cuff-technique. Conclusions This simulation model enables a cost-effective approach for basic training in mouse liver transplantation that can easily be reproduced to reduce animal use in the training process.

BACKGROUND:Surgery has evolved from a hands-on discipline where skills were acquired via the "learning by doing" principle to a surgical science with attention to patient safety, health care effectiveness and evidence-based research. A variety of simulation modalities have been developed to meet the need for effective resident training. So far, research regarding surgical training for minimally invasive surgery has been extensive but also heterogenous in grade of evidence. METHODS:A literature search was conducted to summarize current knowledge about simulation training and to guide research towards evidence-based curricula with translational effects. This was conducted using a variety of terms in PubMed for English articles up to October 2024. Results are presented in a structured narrative review. RESULTS:For virtual reality simulators, there is sound evidence for effective training outcomes. The required instruments for the development of minimally invasive surgery curricula combining different simulation modalities to create a clinical benefit are known and published. CONCLUSION:Surgeons are the main creators for minimally invasive surgery training curricula and often follow a hands-on oriented approach that leaves out equally important aspects of assessment, evaluation, and feedback. Further high-quality research that includes available evidence in this field promises to improve patient safety in surgical disciplines.

Background After intestinal or multivisceral transplant, closing the abdominal wall can be challenging, as negative pressure dressing or synthetic meshes pose risks like infections and fistulas. Clinical practice has evolved from vascularized abdominal wall transplants to non-vascularized Abdominal Rectus Fascia (TxARF). Although it was successful, many immunological aspects remain unknown, highlighting the need for further research. Methods The technique was developed by reproducing the technical aspects of the procedure described for humans in rats (Wistar and Sprague Dawley). Twenty-six Isogenic and Allogeneic TxARF procedures were performed and followed until 30 and 120 post-transplant days (PTD). The non-implanted fascias served as a control group. Rats were then re-assessed for engraftment on 7, 11, 30 and 120 PTD. Fascia samples were taken to assess neovascularization by quantifying cell composition and blood vessels using H&E and Orcein staining. Results All animals (N=26) survived at 30 and 120 PTD, with 4 (15.4 %) developed subcutaneous serum collection. Upon reoperation, grafts showed neovascularization. No adhesions were observed between the intestines and the grafts. The principal cell compound of the fascia was represented by Fibroblasts (18.35 cells/field) and Myocytes (6.57 cells/field). A significant increment of the number of blood vessels were observed during the period studied (p=0.046). Conclusions Our report on TxARF in rats, proves the feasibility of this experimental and translational model, showing similar results to those published in the clinical field. Further studies are required to evaluate the immunogenicity as well as the changes in ARF overtime.