Clinical outcomes and perioperative morbidity and mortality following segmental resections of the colon for Crohn's colitis.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease of a multifactorial pathogenesis. Recently numerous genetic variants linked to an aggressive phenotype were identified, leading to a progress in therapeutic options, resulting in a decreased necessity for surgery. Nevertheless, surgery is often inevitable. The aim of the study was to evaluate possible risk factors for postoperative complications and disease recurrence specifically after colonic resections for CD. PATIENTS AND METHODS: A total of 241 patients who underwent colonic and ileocaecal resections for CD at our instiution between 2008 and 2018 were included. All data was extracted from clinical charts. RESULTS: Major complications occurred in 23.8% of all patients. Patients after colonic resections showed a significantly higher rate of major postoperative complications compared to patients after ICR (p = < 0.0001). The most common complications after colonic resections were postoperative bleeding (22.2%), the need for revision surgery (27.4%) and ICU (17.2%) or hospital readmission (15%). As risk factors for the latter, we identified time interval between admission and surgery (p = 0.015) and the duration of the surgery (p = 0.001). Isolated distal resections had a higher risk for revision surgery and a secondary stoma (p = 0.019). Within the total study population, previous bowel resections (p = 0.037) were identified as independent risk factors for major perioperative complications. CONCLUSION: The results indicate that both a complex surgical site and a complex surgical procedure lead to a higher perioperative morbidity in colonic resections for Crohn's colitis.

Baseline Interleukin-6 as a Preoperative Biomarker for Liver Fibrosis.

Introduction: Liver (hepatic) fibrosis (LF) is characterized by impaired function and regenerative capacity of the liver and can lead to significantly increased morbidity and mortality in the context of surgical liver resection (LR). For this reason, it is crucial to identify the extent of LF preoperatively. Interleukin-6 (IL-6) is known to play a key role in the pathogenesis of LF, but its exact value as a preoperative marker is unknown. This study aimed to investigate the correlation between preoperatively determined IL-6 and the presence of LF. Methods: In this prospective study, IL-6 was determined in 134 consecutive patients undergoing LR. Patients with liver cirrhosis (LC) and patients with clinical or laboratory signs of inflammation were excluded. LF was graded by a blinded pathologist with regard to the degree of LF according to the Desmet classification (0-4). Baseline IL-6 and degree of LF were correlated. Results: A total of 134 patients were prospectively included prior to LR. For 104 patients, LF was graded and inflammatory parameters were available. Thirty-five of these patients showed LC (Desmet 4), and another 33 patients showed preoperatively elevated inflammatory markers. Two of the remaining patients were liver transplant patients. These patients were excluded from the final analysis. According to Desmet, the remaining 34 patients had LF grade 0 or 1 (none or minimal LF) in 26 cases and LF grade 2 or 3 (moderate-to-severe LF) in 8 cases. Correlation of LF with preoperatively determined IL-6 yielded significantly higher IL-6 levels in the group of patients with moderate-to-severe LF (Desmet 2 or 3) compared to the group with none or minimal LF (Desmet 0 or 1; p = 0.0495). Conclusion: In the context of LR, our results showed a correlation of preoperatively determined IL-6 with the extent of LF present. Higher serum baseline IL-6 concentrations were associated with a higher degree of LF, whereas no other blood parameter or score was that predictive for LF. Our results suggest that baseline IL-6 might serve as a valuable parameter to assess LF prior to LR. More patients need to be analyzed to further evaluate and confirm the predictive accuracy of IL-6 for LF.

Effect of Surgery on Postoperative Levels of the Gut Homeostasis-Regulating Enzyme Intestinal Alkaline Phosphatase.

BACKGROUND: Intestinal homeostasis is a crucial factor for complication-free short- and long-term postoperative recovery. The brush border enzyme intestinal alkaline phosphatase (IAP) is an important regulator of gut barrier function and intestinal homeostasis and prevents endotoxemia by detoxifying lipopolysaccharides (LPSs). As IAP is predominantly secreted by enterocytes in the duodenum, we hypothesized that pancreaticoduodenectomy (PD) leads to a significantly stronger decrease in IAP than other major abdominal surgery. STUDY DESIGN: Pre- and postoperative blood, stool, and intestinal samples were collected from patients undergoing PD, as well as other major surgical procedures without duodenectomy. The samples were analyzed using enzyme histochemistry, the para -nitrophenyl phosphate method for IAP, and the limulus amebocyte lysate assay for LPS. RESULTS: Overall, 88 patients were prospectively enrolled in the study. Fecal IAP activity negatively correlated with serum LPS (r = -0.3603, p = 0.0006). PD led to a significant decline in IAP compared to preoperative baseline levels (p < 0.0001). The decline in IAP correlated with the length of proximal small intestinal resection (r = 0.4271, p = 0.0034). Compared to controls, PD was associated with a much more pronounced reduction in IAP-also after adjusting for surgical trauma (operative time, blood loss; r = 0.4598, p = 0.0086). Simultaneously, PD triggered a clearly more prominent increase in serum LPS compared to controls (p = 0.0001). Increased postoperative LPS was associated with an elongated hospitalization (r = 0.7534, p = 0.0062) and more prominent in pancreatic cancer (p = 0.0009). CONCLUSIONS: Based upon the functional roles for IAP, supplementation with exogenous IAP might be a new treatment option to improve short- and long-term outcome after PD.

Differential Immune Infiltration Profiles in Colitis-Associated Colorectal Cancer versus Sporadic Colorectal Cancer.

BACKGROUND: Chronic inflammation is a significant factor in colorectal cancer (CRC) development, especially in colitis-associated CRC (CAC). T-cell exhaustion is known to influence inflammatory bowel disease (IBD) progression and antitumor immunity in IBD patients. This study aimed to identify unique immune infiltration characteristics in CAC patients. METHODS: We studied 20 CAC and 20 sporadic CRC (sCRC) patients, who were matched by tumor stage, grade, and location. Immunohistochemical staining targeted various T-cell markers (CD3, CD4, CD8, and FOXP3), T-cell exhaustion markers (TOX and TIGIT), a B-cell marker (CD20), and a neutrophil marker (CD66b) in tumor and tumor-free mucosa from both groups. The quantification of the tumor immune stroma algorithm assessed immune-infiltrating cells. RESULTS: CAC patients had significantly lower TOX+ cell infiltration than sCRC in tumors (p = 0.02) and paracancerous tissues (p < 0.01). Right-sided CAC showed increased infiltration of TOX+ cells (p = 0.01), FOXP3+ regulatory T-cells (p < 0.01), and CD20+ B-cells (p < 0.01) compared to left-sided CAC. In sCRC, higher tumor stages (III and IV) had significantly lower TIGIT+ infiltrate than stages I and II. In CAC, high CD3+ (p < 0.01) and CD20+ (p < 0.01) infiltrates correlated with improved overall survival. In sCRC, better survival was associated with decreased TIGIT+ cells (p < 0.038) and reduced CD8+ infiltrates (p = 0.02). CONCLUSION: In CAC, high CD3+ and CD20+ infiltrates relate to improved survival, while this association is absent in sCRC. The study revealed marked differences in TIGIT and TOX expression, emphasizing distinctions between CAC and sCRC. T-cell exhaustion appears to have a different role in CAC development.

Humanized NSG Mouse Models as a Preclinical Tool for Translational Research in Inflammatory Bowel Diseases.

The development of animal models reflecting the pathologies of ulcerative colitis (UC) and Crohn's disease (CD) remains a major challenge. The NOD/SCID/IL2rγnull (NSG) mouse strain, which is immune-compromised, tolerates the engraftment of human peripheral blood mononuclear cells (PBMC) derived from patients with UC (NSG-UC) or CD (NSG-CD). This offers the opportunity to examine the impact of individual immunological background on the development of pathophysiological manifestations. When challenged with ethanol, NSG-UC mice exhibited a strong pro-inflammatory response, including the development of edemas, influx of human T cells, B cells and monocytes into the mucosa and submucosa, and elevated expression of the inflammatory markers CRP and CCL-7. Fibrotic alterations were characterized by an influx of fibroblasts and a thickening of the muscularis mucosae. In contrast, the development of pathological manifestations in NSG-CD mice developed without challenge and was signified by extensive collagen deposition between the muscularis propria and muscularis mucosae, as observed in the areas of strictures in CD patients. Vimentin-expressing fibroblasts supplanting colonic crypts and elevated expression of HGF and TGFß corroborated the remodeling phenotype. In summary, the NSG-UC and NSG-CD models partially reflect these human diseases and are powerful tools to examine the mechanism underlying the inflammatory processes in UC and CD.

Molecular characteristics of microsatellite stable early-onset colorectal cancer as predictors of prognosis and immunotherapeutic response.

The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.

An immune-related gene prognostic index for predicting prognosis in patients with colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common solid malignant burdens worldwide. Cancer immunology and immunotherapy have become fundamental areas in CRC research and treatment. Currently, the method of generating Immune-Related Gene Prognostic Indices (IRGPIs) has been found to predict patient prognosis as an immune-related prognostic biomarker in a variety of tumors. However, their role in patients with CRC remains mostly unknown. Therefore, we aimed to establish an IRGPI for prognosis evaluation in CRC. Methods: RNA-sequencing data and clinical information of CRC patients were retrieved from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases as training and validation sets, respectively. Immune-related gene data was obtained from the ImmPort and InnateDB databases. The weighted gene co-expression network analysis (WGCNA) was used to identify hub immune-related genes. An IRGPI was then constructed using Cox regression methods. Based on the median risk score of IRGPI, patients could be divided into high-risk and low-risk groups. To further investigate the immunologic differences, Gene set variation analysis (GSVA) studies were conducted. In addition, immune cell infiltration and related functional analysis were used to identify the differential immune cell subsets and related functional pathways. Results: We identified 49 immune-related genes associated with the prognosis of CRC, 17 of which were selected for an IRGPI. The IRGPI model significantly differentiates the survival rates of CRC patients in the different groups. The IRGPI as an independent prognostic factor significantly correlates with clinico-pathological factors such as age and tumor stage. Furthermore, we developed a nomogram to improve the clinical utility of the IRGPI score. Immuno-correlation analysis in different IRGPI groups revealed distinct immune cell infiltration (CD4+ T cells resting memory) and associated pathways (macrophages, Type I IFNs responses, iDCs.), providing new insights into the tumor microenvironment. At last, drug sensitivity analysis revealed that the high-risk IRGPI group was sensitive to 11 and resistant to 15 drugs. Conclusion: Our study established a promising immune-related risk model for predicting survival in CRC patients. This could help to better understand the correlation between immunity and the prognosis of CRC providing a new perspective for personalized treatment of CRC.

Predictors of outcome for treatment of enterovaginal fistula : Therapeutical strategies for treatment.

BACKGROUND: Enterovaginal fistulas represent a serious complication of various diseases and therapeutic procedures, often associated with complicated clinical courses and massive impairment of quality of life. As underlying conditions and procedures are multifarious, therapeutic approaches are challenging and have to be tailored individually. As the therapeutic management is complex and individualized, multiple surgical interventions might be necessary. METHODS: The aim of this study was to identify possible predictors for outcome in the treatment enterovaginal fistula patients. The study was realized as a retrospective analysis. Ninety-two patients treated with enterovaginal fistulas between 2004 and 2016 were analyzed. Patient characteristics, therapeutic data, and endoscopic findings were stratified according to etiology, closure rate and time, as well as recurrence of fistula. Main outcome measure was the overall rate of fistula closure. RESULTS: Overall therapeutic success rate was 67.4%. Postoperatively derived fistulas were most frequent (40.2%), mainly after rectal surgery (59.5%). Postoperative and non-IBD-inflammation associated fistulas had better outcome than IBD-, radiotherapy-, and tumor-related fistulas (p = 0.001). Successful fistula closure was observed more frequently after radical surgical interventions, best results observed after transabdominal surgery (p < 0.001). Fistula recurrence was also less frequently observed after radical surgical therapies (p = 0.029). A temporary stoma was associated with higher incidence of fistula closure (p = 0.013) and lower incidence of fistula recurrence (p = 0.042) in the postoperative subgroup, as well as shortened therapy period in all groups (p = 0.031). CONCLUSION: Enterovaginal fistulas are a result of various etiologies, and treatment should be adjusted accordingly. A very sustainable, rapid, and persistent therapeutic success can be expected after radical surgical approaches with temporary diverting stoma. This is especially true for postoperatively derived fistulas.

Diagnostic and Therapeutic Management of Early Colorectal Cancer.

Background: Early colorectal cancer (eCRC) is defined as cancer that does not cross the submucosal layer of the colon or rectum, including carcinoma in situ (pTis), pT1a, and pT1b. Early carcinomas differ in their prognosis depending on the risk profile. The differentiation between low and high risk is essential. The low-risk group includes R0-resected, well (G1) or moderately (G2) differentiated tumors without lymphatic vessel invasion (L0), without blood vessel invasion (V0) and a tumor size ≤3 cm. In this constellation, the estimated risk of lymph node metastasis is around 1% or below. The high-risk group includes tumors with incomplete resection (Rx), poor (G3) or undifferentiated (G4) carcinomas, and/or lymphatic and blood vessel invasion (L1) and size ≥3 cm. In a "high-risk" situation, there is a risk for lymph node metastasis of up to 23%. Summary: The incidence of eCRC is rising with a rate of 10% in all endoscopically removed lesions during colonoscopy. For a correct histological evaluation, all suspected lesions should be completely resected. In case of a pT1 lesion in the rectum, pelvic magnetic resonance imaging should be performed to evaluate for suspicious lymph nodes. The therapeutic approach for eCRC is based on histological assessment and ranges from endoscopic resection to radical oncological surgery. The advantages, disadvantages, and associated risks of the individual treatment strategy need to be carefully discussed on a tumor board and with the patient. Key Messages: Treatment options for early colorectal cancer depend on the histological assessment. Poorly differentiated carcinomas, a Kudo ≥ SM2 classified lesion, and a Haggitt level 4 always represent a "high-risk" situation. It should also be mentioned that in rectal cancer, local surgical tumor excision (full-wall excision) is also sufficient for pT1 carcinomas with a "low-risk" constellation (G1/G2; L0, size <3 cm) and an R0 resection.

Smoking as a risk factor for colorectal neoplasms in young individuals? A systematic meta-analysis.

BACKGROUND AND AIMS: Early-onset colorectal neoplasms (EoCRN) include both benign and malign colorectal tumors, which occur before the age of 50. The incidence of EoCRN is rising worldwide. Tobacco smoking has previously been proven to be related to the development of various tumor types. However, its relationship with EoCRN is not clearly defined. Hence, we carried out a systematic review and a meta-analysis to evaluate the relationship between smoking status and the risk of EoCRN. METHODS: A systematic search of PubMed, EMBASE, and Web of Science up to September 7, 2022, was performed for studies that evaluated the association of smoking status with EoCRN. The quality of the case-control study was evaluated with the Newcastle‒Ottawa Scale. The quality of the cross-sectional studies was evaluated with the American Health Care Research and Quality checklist. Fixed-effects models were used to pool odds ratios (ORs) to evaluate the relationship between the risk of developing EoCRN and smoking status. The meta-analyses were performed with Review Manager version 5.4, and funnel plots and publication bias tests were produced by STATA software. RESULTS: A total of six studies were included in this meta-analysis. After pooling the results of these six studies, we found that current smokers carry a relatively high risk of developing EoCRN (OR, 1.33; 95% confidence interval [CI], 1.17-1.52) compared to never-smokers. Ex-smokers were not at a significantly increased risk for developing EoCRN (OR, 1.00; 95% CI, 0.86-1.18). DISCUSSION: Smoking behavior is significantly associated with an increased risk for developing EoCRN and might be one of the reasons for the increasing incidence. Ex-smokers who quit are not at significant risk of developing EoCRN.

Gut Barrier Dysfunction and Bacterial Lipopolysaccharides in Colorectal Cancer.

BACKGROUND: Inflammation is known to be an essential driver of various types of cancer. An increasing number of studies have suggested that the occurrence and development of colorectal cancer (CRC) are linked to the inflammatory microenvironment of the intestine. This assumption is further supported by the fact that patients with inflammatory bowel disease (IBD) are more likely to develop CRC. Multiple studies in mice and humans have shown that preoperative systemic inflammatory response is predictive of cancer recurrence after potentially curative resection. Lipopolysaccharides (LPS) are membrane surface markers of gram-negative bacteria, which induce gut barrier dysfunction and inflammation and might be significantly involved in the occurrence and development of CRC. METHODS: A selective literature search was conducted in Medline and PubMed, using the terms "Colorectal Cancer", "Gut Barrier", "Lipopolysaccharides", and "Inflammation". RESULTS: Disruption of intestinal homeostasis, including gut barrier dysfunction, is linked to increased LPS levels and is a critical factor for chronic inflammation. LPS can activate the diverse nuclear factor-κB (NF-κB) pathway via Toll-like receptors 4 (TLR4) to promote the inflammatory response, which aggravates gut barrier dysfunction and encourages CRC development. An intact gut barrier prevents antigens and bacteria from crossing the intestinal endothelial layer and entering circulation. In contrast, a damaged gut barrier triggers inflammatory responses and increases susceptibility to CRC. Thus, targeting LPS and the gut barrier might be a promising novel therapeutic approach for additional treatment of CRC. CONCLUSION: Gut barrier dysfuction and bacterial LPS seem to play an important role in the pathogenesis and disease progression of colorectal cancer and therefore require further investigation.

The Role of Microbiota in Liver Transplantation and Liver Transplantation-Related Biliary Complications.

Liver transplantation as a treatment option for end-stage liver diseases is associated with a relevant risk for complications. On the one hand, immunological factors and associated chronic graft rejection are major causes of morbidity and carry an increased risk of mortality due to liver graft failure. On the other hand, infectious complications have a major impact on patient outcomes. In addition, abdominal or pulmonary infections, and biliary complications, including cholangitis, are common complications in patients after liver transplantation and can also be associated with a risk for mortality. Thereby, these patients already suffer from gut dysbiosis at the time of liver transplantation due to their severe underlying disease, causing end-stage liver failure. Despite an impaired gut-liver axis, repeated antibiotic therapies can cause major changes in the gut microbiome. Due to repeated biliary interventions, the biliary tract is often colonized by several bacteria with a high risk for multi-drug resistant germs causing local and systemic infections before and after liver transplantation. Growing evidence about the role of gut microbiota in the perioperative course and their impact on patient outcomes in liver transplantation is available. However, data about biliary microbiota and their impact on infectious and biliary complications are still sparse. In this comprehensive review, we compile the current evidence for the role of microbiome research in liver transplantation with a focus on biliary complications and infections due to multi-drug resistant germs.

Metabolic Role of Autophagy in the Pathogenesis and Development of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins resulting from abnormal wound repair response and metabolic disorders. Various metabolic factors play crucial roles in the progression of NAFLD, including abnormal lipid, bile acid, and endotoxin metabolism, leading to chronic inflammation and hepatic stellate cell (HSC) activation. Autophagy is a conserved process within cells that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Accumulating evidence has shown the importance of autophagy in NAFLD and its close relation to NAFLD progression. Thus, regulation of autophagy appears to be beneficial in treating NAFLD and could become an important therapeutic target.

The cathepsin-S/protease-activated receptor-(PAR)-2 axis drives chronic allograft vasculopathy and is a molecular target for therapeutic intervention.

BACKGROUND: Cathepsin S (CatS) and proteinase-activated receptor (PAR)-2 are involved in the remodelling of vascular walls and neointima formation as well as in alloantigen presentation and T-cell priming. Therefore, we hypothesized that CatS/PAR-2 inhibition/deficiency would attenuate chronic allograft vasculopathy. METHODS: Heterotopic aortic murine transplantation was performed from C57BL/6J donors to C57BL/6J recipients (syngeneic control group), Balb/c to C57BL/6J without treatment (allogenic control group), Balb/c to C57BL/6J with twice daily oral CatS inhibitor (allogenic treatment group) and Balb/c to Par2-/- C57BL/6J (allogenic knockout group). The recipients were sacrificed on day 28 and the grafts were harvested for histological analysis and RT-qPCR. RESULTS: After 28 days, mice of the allogenic control group exhibited significant neointima formation and massive CD8 T-cell infiltration into the neointima while the syngeneic control group showed negligible allograft vasculopathy. The mRNA expression level of CatS in allografts was 5-fold of those in syngeneic grafts. Neointima formation and therefore intima/media-ratio were significantly decreased in the treatment and knockout group in comparison to the allogenic control group. Mice in treatment group also displayed significantly fewer CD8 T cells in the neointima compared with allogeneic controls. Additionally, treatment with the CatS inhibitor and PAR2-deficiency decreased mRNA-levels of interleukins and cytokines. CONCLUSION: In conclusion, our data indicate that inhibiting CatS and PAR-2 deficiency led to a marked reduction of neointima formation and associated inflammation in a murine heterotopic model for allograft vasculopathy.

Measuring Young's modulus of single trabeculae in cancellous bone using a two-point bending test.

BACKROUND: Surgical treatment of proximal humeral fractures poses a major challenge, especially in osteoporotic bone. At present, there appears to exist neither a suitable model for research to optimize the osteosynthesis processes nor are the structural data available which are required for developing such a model. Therefore, the aim of this study is to determine the microscopic morphology and Young's modulus of cancellous bone from human humeral heads considering osteoporotic changes. METHODS: Cylindrical samples were taken from ten fresh-frozen human humeral heads and structural analysis was done with µCT. Ten rod-like trabeculae were prepared from five of the humeral heads each which were measured and tested mechanically. For this purpose, the trabeculae were fixed on a slide and rotated axially under a stereo microscope. The sample cross-section and the depending moment of inertia were extracted from the image data. The samples were then loaded in a 2-point bending test and Young's moduli of the samples were determined. RESULTS: It could be shown that with increasing age of the donor, ossified portion of the cancellous bone decreased (p < 0.05). The average degree of mineralization of the bone was 1.24 (±0.06) g/mm3, which decreased with increasing age (p < 0.05). The determined Young's modulus averaged 1.33 (±1.76) GPa. INTERPRETATION: The verified structural parameter showed osteoporotic changes in the examined bone. This study for the first time determined Young's modulus of single trabeculae of cancellous bone of osteoporotically altered human humeral heads. Implementing the non-destructive sample measurement before exposure resulted in a methodical improvement.

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

[Expected effects of the new continuing education regulations in general and visceral surgery : Survey among Bavarian surgeons and residents]. / Erwartete Effekte der neuen Weiterbildungsordnung in der Allgemein- und Viszeralchirurgie : Eine Umfrage unter bayerischen Chirurg*innen und Weiterbildungsassistent*innen.

INTRODUCTION: The new competency-based continuing education regulations for surgical training (WBO) came into effect in Bavaria in August 2022. METHODS: From May to July 2022, we conducted an anonymized online survey among Bavarian general and visceral surgeons and surgical residents (ÄiW). The aim was to survey expectations of the effects of the new WBO. RESULTS: The response rate was 35%. In total data could be collected from 80 persons, 36 ÄiW (45%), 30 specialists and senior physicians (37.5%) and 14 chief physicians (17.5%). The majority of respondents worked at a university hospital (38.8%) or a regular provider (35%). A strengthening of the competence to act through implementation of the new WBO is seen by 41.3% and 55.7% see independent operating under partial supervision by the instructor as a goal. Of the respondents 50% see the required case numbers as not achievable and 55.1% deny reaching them in the expected period of 6 years. About 60% do not expect to be able to train the same number of ÄiWs in the same amount of time. Almost 75% of the respondents state that from their point of view, a good continuing education with the achievement of a solid competence to act would not work without overtime hours. About 44% of the respondents expect that a full surgical training would continue to be possible at their institution. CONCLUSION: Both among the instructors and among the trainees there is a tendency to fear that realistic training, in particular the achievement of the guideline figures, will no longer be possible in the usual further training time. This necessitates the consistent implementation of structured continuing education with a high degree of transparency in training.

Analysis of Circulating Immune Subsets in Primary Colorectal Cancer.

The development and progression of colorectal cancer (CRC) are known to be affected by the interplay between tumor and immune cells. However, the impact of CRC cells on the systemic immunity has yet to be elucidated. We aimed to comprehensively evaluate the circulating immune subsets and transcriptional profiles of CRC patients. In contrast to healthy controls (HCs), CRC patients had a lower percentage of B and T lymphocytes, T helper (Th) cells, non-classical monocytes, dendritic cells, and a higher proportion of polymorphonuclear myeloid-derived suppressor cells, as well as a reduced expression of CD69 on NK cells. Therefore, CRC patients exhibit a more evident systemic immune suppression than HCs. A diagnostic model integrating seven immune subsets was constructed to distinguish CRC patients from HCs with an AUC of 1.000. Moreover, NR3C2, CAMK4, and TRAT1 were identified as candidate genes regulating the number of Th cells in CRC patients. The altered composition of circulating immune cells in CRC could complement the regional immune status of the tumor microenvironment and contribute to the discovery of immune-related biomarkers for the diagnosis of CRC.

It is not NOD2 - genetic and clinical risk factors for postoperative complications following ileocolic resection in Crohn's disease.

PURPOSE: To evaluate the role of the nucleotide oligomerization domain 2 (NOD2) mutation status and other risk factors for the incidence of postoperative complications after ileocolic resection for Crohn's disease (CD). METHODS: Data of 138 patients consecutively undergoing ileocolic resection for CD at a tertiary academic referral center were retrospectively analyzed including single nucleotide polymorphism (SNP) data of the NOD2 gene. Uni- and multivariate regression analysis was performed to identify factors associated with increased risk of severe postoperative complications. RESULTS: From 114 patients (83%), the NOD2 mutation status was available. Of these, 60 (53%) had a NOD2 wildtype, whereas eleven (10%) were homozygous for the high risk p.Leu1007fsX1008 (rs2066847) variant. Major postoperative complications occurred in 28 patients (20%). Twenty-seven of these (96%) were intraabdominal septic complications such as anastomotic leakage or abscess. Male gender (P = 0.029; OR 3.052, the duration of CD (time [months] from initial diagnosis of CD to surgery; P = 0.001; OR 1.009), previous abdominal surgery for CD (P = 0.017; OR 3.49), and the presence of enteric fistulas (P = 0.023; OR 3.21) were identified as independent risk factors for major postoperative complications. Homozygosity for the NOD2 high-risk variant p.Leu1007fsX1008 did not show increased postoperative morbidity in the short and long-term outcome. CONCLUSIONS: We could detect independent risk factors for major postoperative complications after ileocolic resection for Crohn's disease. However, patients with the high-risk variant p.Leu1007fsX1008 of the NOD2 gene did not show increased postoperative morbidity.

Determination of E-modulus of cancellous bone derived from human humeri and validation of plotted single trabeculae: Development of a standardized humerus bone model.

Background: Evaluation of the mechanical behavior of the microstructure of cancellous bone seems important for the understanding of the mechanical behavior of bone. Prevention and treatment of fragility fractures due to osteoporosis is a major challenge according to ageing population. A bone model might help to assess fracture risk. Measurement of single trabeculae of bone should give further information compared with bone densitometry alone. This study measures the mechanical properties of single cancellous trabeculae derived from human proximal humerus. Methods: 34 single trabeculae dissected from human humeral heads were measured and evaluated mechanically. Trabeculae were fixed on microscope slides and geometrical data were reported during axial rotation of the specimens to measure the transverse section using computer aided design (CAD). The samples were subjected to a two-point bending test and were loaded with a measure-stamp at a defined distance. Force and deflection were measured by high-resolution sensors. The E-modulus was then calculated in combination with finite elements method simulation (FEM), using the previously obtained CAD-Data. Results: The average E-modulus from 34 valid measurements of human humeral trabeculae was 1678 MPa with a range from 829 to 3396 MPa, which is consistent with existing literature. The planned additional validation of the measurement method using manufactured three-dimensional synthetic trabeculae with known mechanical properties showed an average elastic modulus of single trabeculae of 51.5 MPa, being two dimensions lower than the value reported in the datasheet of the plastic. Conclusion: This newly developed, time and cost-efficient procedure allows the measurement of E-modulus in single trabeculae. Measurement of mechanic parameters of single trabeculae might give insights on mechanic behavior of bone and be relevant for the research of systemic bone diseases, complementing the existing data on bone-mineral-density. Further examination of single trabeculae of human cancellous bone should give an insight on the mechanical behavior of bone also considering systemic bone diseases.