Background: Bariatric surgery has been shown to improve the histopathological findings in patients with obesity and metabolic dysfunction-associated steatohepatitis, but there are also reports about non-responders or progressive disease after bariatric interventions. Therefore, it is of utmost importance to understand the pathophysiological processes in the liver after bariatric surgery. Materials and methods: In the present study, 4 weeks old male C57/Bl6 mice were fed a Western Diet to induce metabolic dysfunction-associated steatohepatitis and sleeve-gastrectomy (SG), or sham operation in the pair-fed and ad libitum control group were performed. Mice were observed for two or eight weeks after surgery and metabolic assessment was performed throughout the experiment. Histopathology, flow cytometry and proteomic analyses were conducted to evaluate hepatic inflammation, liver metabolism and affected signaling pathways. Results: Weight loss was higher, and metabolism significantly improved after SG. Two weeks after SG major inflammatory and regulatory disturbances in the liver were observed. The proportion of hepatic CD3+NK1.1+ cells were decreased, and proteins involved in apoptosis like Fas, Casp1 and Casp9 or in the acute phase response were upregulated in SG mice. These disturbances decreased in the long-term and we observed an increase of many proteins involved in lipid metabolism eight weeks following SG. Conclusions: The rapid weight loss and decrease of hepatic fat after SG lead to a proinflammatory response in the liver in the early phase after surgery, which changes to a more moderate immune response in the long-term. We suggest a preoperative risk stratification and postoperative surveillance depending on the histopathological findings.

Background: Synthetic mesh material is of great importance for surgical incisional hernia repair. The physical and biochemical characteristics of the mesh influence mechanical stability and the foreign body tissue reaction. The influence on bacterial infections, however, remains ill-defined. The aim of the present study was to evaluate the influence of a modified mesh structure with variation in filament linking on the occurrence of bacterial infection that is indicated by the occurrence of CD68+, CD4+, and CD8+ cells in two different materials. Methods: A total of 56 male Sprague Dawley rats received a surgical mesh implant in a subcutaneous abdominal position. The mesh of two different polymers (polypropylene (PP) and polyvinylidenfluoride (PVDF)) and two different structures (standard structure and bold structure with higher filament linking) were compared. During the implantation, the meshes were infected with Staphylococcus (S.) aureus. After 7 and 21 days, meshes were explanted, and the early and late tissue responses to infection were histologically evaluated. Results: Overall, the inflammatory tissue response was higher at 7 days when compared to 21 days. At 7 days, PP meshes of the standard structure (PP-S) showed the strongest inflammatory tissue response in comparison to all the other groups. At 21 days, no statistically significant difference between different meshes was detected. CD8+ cytotoxic T cells showed a significant difference at 21 days but not at 7 days. PP meshes of both structures showed a higher infiltration of CD8+ T cells than PVDF meshes. CD4+ T helper cells differed at 7 days but not at 21 days, and PVDF meshes in a bold structure showed the highest CD4+ T cell count. The number of CD68+ macrophages was also significantly higher in PP meshes in a standard structure when compared to PVDF meshes at 21 days. Conclusion: The inflammatory tissue response to S. aureus infection appears to be highest during the early period after mesh implantation. PP meshes showed a higher inflammatory response than PVDF meshes. The mesh material appears to be more important for the risk of infection than the variation in filament linking.

Study design A randomized, controlled, prospective multicenter clinical trial with a parallel group design was initiated in eight surgical centers to compare a large-pore polypropylene mesh (Ultrapro ® ) to a small-pore polypropylene mesh (Premilene ® ) within a standardized retromuscular meshplasty for incisional hernia repair. Methods Between 2004 and 2006, patients with a fascial defect with a minimum diameter of 4 cm after vertical midline laparotomy were recruited for the trial. Patients underwent retromuscular meshplasty with either a large-pore or a small-pore mesh to identify the superiority of the large-pore mesh. Follow-up visits were scheduled at 5 and 21 days and 4, 12, and 24 months after surgery. A clinical examination, a modified short form 36 (SF-36 ® ), a daily activity questionnaire, and an ultrasound investigation of the abdominal wall were completed at every follow-up visit. The primary outcome criterion was foreign body sensation at the 12-month visit, and the secondary endpoint criteria were the occurrence of hematoma, seroma, and chronic pain within 24 months postoperatively. Results In 8 centers, 181 patients were included in the study. Neither foreign body sensation within the first year after surgery (27.5% Ultrapro ® , 32.2% Premilene ® ) nor the time until the first occurrence of foreign body sensation within the first year was significantly different between the groups. Regarding the secondary endpoints, no significant differences could be observed. At the 2-year follow-up, recurrences occurred in 5 Ultrapro ® patients (5.5%) and 4 Premilene ® patients (4.4%). Conclusion Despite considerable differences in theoretical and experimental works, we have not been able to identify differences in surgical or patient-reported outcomes between the use of large- and small-pore meshes for retromuscular incisional hernia repair. Trial registration Clinical Trials NCT04961346 (16.06.2021) retrospectively registered.

BACKGROUND:Eftilagimod alpha (efti) is a major histocompatibility complex class II agonist activating antigen-presenting cells which leads to greater systemic type 1 T helper response and more cytotoxic CD8+ T-cell activation. This phase I trial evaluated the administration of efti, a soluble lymphocyte activation gene-3 (LAG-3) protein, combined with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab in advanced solid tumors.PATIENTS AND METHODS:Patients with heavily pretreated metastatic solid tumors received intravenous avelumab (800 mg) combined with subcutaneously administered efti (6 or 30 mg) for up to 12 cycles, followed by avelumab monotherapy. The primary endpoint was the assessment of the recommended phase II dose (RP2D) of efti in combination with avelumab.RESULTS:Twelve patients with different tumor entities were enrolled (six patients in each cohort). During treatment, no dose-limiting toxicities occurred, and the severity of most adverse events was grade 1 or 2. In total, nine serious adverse events were documented, resulting in a fatal outcome in two cases, but none of them were assessed to be treatment related. Five patients (42%) achieved partial response. The median progression-free survival was 1.96 months and the median overall survival was not reached, with a 12-month survival rate of 75%.CONCLUSION:Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

Background Computerized radiological image analysis (radiomics) enables the investigation of image-derived phenotypes by extracting large numbers of quantitative features. We hypothesized that radiomics features may contain prognostic information that enhances conventional body composition analysis. We aimed to investigate whether body composition-associated radiomics features hold additional value over conventional body composition analysis and clinical patient characteristics used to predict survival of pancreatic ductal adenocarcinoma (PDAC) patients. Methods Computed tomography images of 304 patients undergoing elective pancreatic cancer resection were analysed. 2D radiomics features were extracted from skeletal muscle and subcutaneous and visceral adipose tissue (SAT and VAT) compartments from a single slice at the third lumbar vertebra. The study population was randomly split (80:20) into training and holdout subsets. Feature ranking with Least Absolute Shrinkage Selection Operator (LASSO) followed by multivariable stepwise Cox regression in 1000 bootstrapped re-samples of the training data was performed and tested on the holdout data. The fitted regression predictors were used as “scores” for a clinical (C-Score), body composition (B-Score), and radiomics (R-Score) model. To stratify patients into the highest 25% and lowest 25% risk of mortality compared to the middle 50%, the Harrell Concordance Index was used. Results Based on LASSO and stepwise cox regression for overall survival, ASA ≥3 and age were the most important clinical variables and constituted the C-score, and VAT-index (VATI) was the most important body composition variable and constituted the B-score. Three radiomics features (SATI_original_shape2D_Perimeter, VATI_original_glszm_SmallAreaEmphasis, and VATI_original_firstorder_Maximum) emerged as the most frequent set of features and yielded an R-Score. Of the mean concordance indices of C-, B-, and R-scores, R-score performed best (0.61, 95% CI 0.56–0.65, p<0.001), followed by the C-score (0.59, 95% CI 0.55-0.63, p<0.001) and B-score (0.55, 95% CI 0.50–0.60, p=0.03). Kaplan-Meier projection revealed that C-, B, and R-scores showed a clear split in the survival curves in the training set, although none remained significant in the holdout set. Conclusion It is feasible to implement a data-driven radiomics approach to body composition imaging. Radiomics features provided improved predictive performance compared to conventional body composition variables for the prediction of overall survival of PDAC patients undergoing primary resection.

This study aimed to observe the impact of the COVID-19 outbreak on acute general surgery in the first German “hotspot” regions of Heinsberg and Aachen, during the first months of the pandemic. The incidence and severity of acute appendicitis, acute cholecystitis and mechanical bowel obstruction, were compared between March and May 2020 and a control period (same months of the previous three years). Pre-, intra- and postoperative data was compared between three regional hospitals of Heinsberg and the closest maximum care, university hospital. A total of 592 operated patients were included, 141 belonging to the pandemic cohort and 451 to the historic cohort. The pandemic group showed higher rates of clinical peritonitis (38% vs. 27%, p = 0.015), higher rates of mean white blood cell count (13.2±4.4 /nl vs. 12.3±4.7 /nl, p = 0.044) and mean C-reactive protein (60.3±81.1 mg/l vs. 44.4±72.6 mg/l, p = 0.015) preoperatively. Specifically in patients with acute appendicitis, there were less patients with catarrhal appendicitis (23% vs. 35%, p = 0.021) and a tendency towards more advanced histological findings in the pandemic cohort. In the university hospital, a 42% reduction in acute operated cases was observed at the onset of the pandemic (n = 30 in 2020 vs. n = 52 in 2019), whereas in the peripheral hospitals of Heinsberg there was only a 10% reduction (n = 111 in 2020 vs. n = 123 in 2019). The onset of the COVID-19 pandemic in our region was accompanied by advanced preoperative and intraoperative findings in patients undergoing emergency general surgery. A greater reduction in acute operated surgical cases was observed at the university hospital, in contrast to the smaller hospitals of Heinsberg, suggesting a possible shift of emergency patients, requiring immediate operation, from maximum care hospital to the periphery.

Die innovative Entwicklung diagnostischer und therapeutischer Möglichkeiten führen zu einer zunehmenden Komplexität der onkologischen Behandlung. Bei einigen Patienten eröffnet daher die Einholung einer Zweitmeinung in spezialisierten Zentren neue Therapieoptionen. Diese kann sowohl vonseiten des Patienten als auch des Behandlers initiiert werden. Wissenschaftliche Arbeiten aus den letzten Jahren konnten u. a. zeigen, dass eine Zweitmeinung zur Änderung der Diagnose und der Therapieempfehlung bei einer signifikanten Anzahl von Patienten führt. Neuere Untersuchungen deuten zudem darauf hin, dass sich dies auch in einer verbesserten Prognose niederschlägt, wenn die Behandlungsempfehlungen der Zweitmeinung berücksichtigt wurden. Die Einholung einer Zweitmeinung sollte daher als Instrument zur Verbesserung der Versorgung bei Patienten mit komplexer onkologischer Erkrankung in Betracht gezogen werden.

Obesity and associated nonalcoholic steatohepatitis (NASH) are on the rise globally. NASH became an important driver of hepatocellular carcinoma (HCC) in recent years. Activation of the central metabolic regulator mTOR (mechanistic target of rapamycin) is frequently observed in HCCs. However, mTOR inhibition failed to improve the outcome of HCC therapies, demonstrating the need for a better understanding of the molecular and functional consequences of mTOR blockade. We established a murine NASH-driven HCC model based on long-term western diet feeding combined with hepatocellular mTOR-inactivation. We evaluated tumor load and whole-body fat percentage via µCT-scans, analyzed metabolic blood parameters and tissue proteome profiles. Additionally, we used a bioinformatic model to access liver and HCC mitochondrial metabolic functions. The tumor burden was massively increased via mTOR-knockout. Several signs argue for extensive metabolic reprogramming of glucose, fatty acid, bile acid and cholesterol metabolism. Kinetic modeling revealed reduced oxygen consumption in KO-tumors. NASH-derived HCC pathogenesis is driven by metabolic disturbances and should be considered separately from those caused by other etiologies. We conclude that mTOR functions as tumor suppressor in hepatocytes especially under long-term western diet feeding. However, some of the detrimental consequences of this diet are attenuated by mTOR blockade.

Stratum C of the INSIGHT platform trial evaluates eftilagimod alpha (efti) combined with standard of care (SOC) 1st line chemo-immunotherapy (IC) in metastatic NSCLC patients (pts). Efti is an MHC class II agonist (soluble LAG-3 protein) activating antigen-presenting cells followed by T-cell (CD4/CD8) activation. Efti aims to enhance efficacy of IC. Pts with 1st line advanced or metastatic NSCLC adenocarcinomas (non-squamous) receive carboplatin AUC5 / pemetrexed 500 mg/m2 q3w 4 cycles followed by optional pemetrexed 500 mg/m2 q3w maintenance plus pembrolizumab 200 mg q3w combined with s.c. efti (30 mg) (q2w for 24 weeks; thereafter q3w till week 52). Imaging: q8w. Primary endpoint: feasibility (safety / tolerability). Secondary endpoints include ORR (RECIST 1.1.), PFS, OS. From 02Aug2021 till data cut off 18Apr2023 21 pts were enrolled and received treatment (median age: 65 years; 66.7% male). No occurrence of unacceptable toxicities. 10 SAE (grade 1-2: 3; grade 3: 4; grade 4: 0; grade 5: 3) were reported. 1 pancreatitis was possibly related to efti (or immunotherapy in general) and unexpected. So far, 4 pts completed max. treatment with efti for 52 weeks. The most frequent AEs were anemia in 18 pts (52.4%, grade 1-2 and 33.3%, grade 3), neutropenia in 18 pts (19.0%, grade 2 and 66.7%, grade 3-4), leukopenia in 16 pts (28.6%, grade 1-2 and 47.6%, grade 3-4) and thrombocytopenia in 14 pts (42.9%, grade 1-2 and 23.8%, grade 3-4). 5 AEs with grade 3 and no AE with grade 4 and 5 were considered related to efti. Out of 21 pts, 14 pts (67%) showed partial response, 5 (24%) stable disease, 2 (9%) progressive disease as BOR. Even pts with negative or low PD-L1 status (TPS) showed promising efficacy signals. Median follow up: 8.3 months, median OS: not reached. To date, 30 mg efti combined with SOC appears to be feasible and safe with promising signals of efficacy, so that the trial was amended for inclusion of further 30 pts.

Laparoscopic hepatectomy (LH) is nowadays considered as the standard of care for various liver malignancies. However, studies focusing on perioperative outcome after LH in patients with severe comorbidities are still sparse.

(1) Introduction: The intraperitoneal onlay mesh technique (IPOM) is widely used to repair incisional hernias. This method has advantages but suffers from complications due to intraperitoneal adhesion formation between the mesh and intestine. An ideal mesh minimizes adhesions and shows good biocompatibility. To address this, newly developed multifilamentous polyethylene (PET) meshes were constructed from sub-macrophage-sized monofilaments and studied regarding biocompatibility and adhesion formation. (2) Methods: We investigated fine (FPET, 72 filaments, 11 µm diameter each) and ultra-fine multifilament (UFPET, 700 filaments, 3 µm diameter each) polyethylene meshes for biocompatibility in subcutaneous implantation in rats. Adhesion formation was analyzed in the IPOM position in rabbits. Geometrically identical mono-filamentous polypropylene (PP) Bard Soft® PP meshes were used for comparison. Histologic and immune-histologic foreign body reactions were assessed in 48 rats after 7 or 21 days (four mesh types, with two different mesh types per rat; n = 6 per mesh type). Additionally, two different mesh types each were placed in the IPOM position in 24 rabbits to compile the Diamond peritoneal adhesion score after the same timeframes. The biocompatibility and adhesion score differences were analyzed with the Kruskal–Wallis nonparametric statistical test. (3) Results: Overall, FPET and, especially, UFPET showed significantly smaller foreign body granulomas compared to PP meshes. Longer observation periods enhanced the differences. Immunohistology showed no significant differences in the cellular immune response and proliferation. UFPET demonstrated significantly reduced peritoneal adhesion formation compared to all other tested meshes after 21 days. (4) Conclusions: Overall, FPET and, especially, UFPET demonstrated their suitability for IPOM hernia meshes in animal models by improving major aspects of the foreign body reaction and reducing adhesion formation.

Gastrointestinal anastomoses are an important source of postoperative complications. In particular, the ideal suturing material is still the subject of investigation. Therefore, this study aimed to evaluate a newly developed suturing material with elastic properties made from thermoplastic polyurethane (TPU); Polyvinylidene fluoride (PVDF) and TPU were tested in two different textures (round and a modified, "snowflake" structure) in 32 minipigs, with two anastomoses of the small intestine sutured 2 m apart. After 90 days, the anastomoses were evaluated for inflammation, the healing process, and foreign body reactions. A computer-assisted immunohistological analysis of staining for Ki67, CD68, smooth muscle actin (SMA), and Sirius red was performed using TissueFAXS. Additionally, the in vivo elastic properties of the material were assessed by measuring the suture tension in a rabbit model. Each suture was tested twice in three rabbits; No major surgical complications were observed and all anastomoses showed adequate wound healing. The Ki67+ count and SMA area differed between the groups (F (3, 66) = 5.884, p = 0.0013 and F (3, 56) = 6.880, p = 0.0005, respectively). In the TPU-snowflake material, the Ki67+ count was the lowest, while the SMA area provided the highest values. The CD68+ count and collagen I/III ratio did not differ between the groups (F (3, 69) = 2.646, p = 0.0558 and F (3, 54) = 0.496, p = 0.686, respectively). The suture tension measurements showed a significant reduction in suture tension loss for both the TPU threads; Suturing material made from TPU with elastic properties proved applicable for intestinal anastomoses in a porcine model. In addition, our results suggest a successful reduction in tissue incision and an overall suture tension homogenization.

Appendectomy for acute appendicitis is one of the most common operative procedures worldwide in both children and adults. In particular, complicated (perforated) cases show high variability in individual outcomes. Here, we developed and validated a machine learning prediction model for postoperative outcome of perforated appendicitis. Retrospective analyses of patients with clinically and histologically verified perforated appendicitis over 10 years were performed. Demographic and surgical baseline characteristics were used as competing predictors of single-patient outcomes along multiple dimensions via a random forest classifier with stratified subsampling. To assess whether complications could be predicted in new, individual cases, the ensuing models were evaluated using a replicated 10-fold cross-validation. A total of 163 patients were included in the study. Sixty-four patients underwent laparoscopic surgery, whereas ninety-nine patients got a primary open procedure. Interval from admission to appendectomy was 9 ± 12 h and duration of the surgery was 74 ± 38 min. Forty-three patients needed intensive care treatment. Overall mortality was 0.6 % and morbidity rate was 15%. Severe complications as assessed by Clavien-Dindo > 3 were predictable in new cases with an accuracy of 68%. Need for ICU stay (> 24 h) could be predicted with an accuracy of 88%, whereas prolonged hospitalization (greater than 7–15 days) was predicted by the model with an accuracy of 76%. We demonstrate that complications following surgery, and in particular, health care system-related outcomes like intensive care treatment and extended hospitalization, may be well predicted at the individual level from demographic and surgical baseline characteristics through machine learning approaches.

Activation of the mechanistic target of rapamycin (mTOR) pathway is frequently found in cancer, but mTOR inhibitors have thus far failed to demonstrate significant antiproliferative efficacy in the majority of cancer types. Besides cancer cell-intrinsic resistance mechanisms, it is conceivable that mTOR inhibitors impact on non-malignant host cells in a manner that ultimately supports resistance of cancer cells. Against this background, we sought to analyze the functional consequences of mTOR inhibition in hepatocytes for the growth of metastatic colon cancer. To this end, we established liver epithelial cell (LEC)-specific knockout (KO) of mTOR (mTORLEC ) mice. We used these mice to characterize the growth of colorectal liver metastases with or without partial hepatectomy to model different clinical settings. Although the LEC-specific loss of mTOR remained without effect on metastasis growth in intact liver, partial liver resection resulted in the formation of larger metastases in mTORLEC mice compared with wildtype controls. This was accompanied by significantly enhanced inflammatory activity in LEC-specific mTOR KO livers after partial liver resection. Analysis of NF-ĸB target gene expression and immunohistochemistry of p65 displayed a significant activation of NF-ĸB in mTORLEC mice, suggesting a functional importance of this pathway for the observed inflammatory phenotype. Taken together, we show an unexpected acceleration of liver metastases upon deletion of mTOR in LECs. Our results support the notion that non-malignant host cells can contribute to resistance against mTOR inhibitors and encourage testing whether anti-inflammatory drugs are able to improve the efficacy of mTOR inhibitors for cancer therapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Background Patients with inflammatory bowel disease (IBD) have a high-life time risk undergoing abdominal surgery and are prone to develop incisional hernias (IH) in the postoperative course. Therefore, we investigated the role of IBD as perioperative risk factor in open ventral hernia repair (OVHR) as well as the impact of IBD on hernia recurrence during postoperative follow-up. Methods The postoperative course of 223 patients (Non-IBD (n = 199) and IBD (n = 34)) who underwent OVHR were compared by means of extensive group comparisons and binary logistic regressions. Hernia recurrence was investigated in the IBD group according to the Kaplan–Meier method and risk factors for recurrence determined by Cox regressions. Results General complications (≥ Clavien-Dindo I) occurred in 30.9% (72/233) and major complications (≥ Clavien-Dindo IIIb) in 7.7% (18/233) of the overall cohort with IBD being the single independent risk-factor for major complications (OR = 4.2, p = 0.007). Further, IBD patients displayed a recurrence rate of 26.5% (9/34) after a median follow-up of 36 months. Multivariable analysis revealed higher rates of recurrence in patients with ulcerative colitis (UC, 8/15, HR = 11.7) compared to patients with Crohn’s disease (CD, 1/19, HR = 1.0, p = 0.021). Conclusion IBD is a significant risk factor for major postoperative morbidity after OVHR. In addition, individuals with IBD show high rates of hernia recurrence over time with UC patients being more prone to recurrence than patients with CD.

BACKGROUND Laparoscopic liver surgery is currently considered the standard of care for various liver malignancies. However, studies focusing on perioperative outcome after laparoscopic hepatectomy (LH) in overweight patients are still sparse and its benefit compared to open hepatectomy (OH) is a matter of debate. AIM To analyze postoperative outcomes in overweight [body mass index (BMI) over 25 kg/m²] and obese (BMI over 30 kg/m²) patients undergoing LH and compare postoperative outcome with patients undergoing OH. METHODS Perioperative data of 68 overweight (BMI over 25 kg/m²) including a subcohort of obese (BMI over 30 kg/m²) patients (n = 27) who underwent LH at our institution between 2015 and 2019 were retrospectively analyzed regarding surgical outcome and compared to an equal number of patients undergoing OH. RESULTS The mean BMI was 29.8 ± 4.9 kg/m2 in the LH group and 29.7 ± 3.6 kg/m2 in the OH group with major resections performed in 20.6% (LH) and 26.5% (OH) of cases, respectively. Operative time (194 ± 88 min vs 275 ± 131 min; P < 0.001) as well as intensive care (0.8 ± 0.7 d vs 1.1 ± 0.8 d; P = 0.031) and hospital stay (7.3 ± 3.6 d vs 15.7 ± 13.5 d; P < 0.001) were significant shorter in the LH group. Also, overall complications (20.6% vs 45.6%; P = 0.005) and major complications (1.5% vs 14.7%, P = 0.002) were observed less frequently after LH. An additional investigation analyzing the subgroup of obese patients who underwent LH (n = 27) and OH (n = 29) showed a shorter operative time (194 ± 81 min vs 260 ± 137 min; P = 0.009) and a reduced length of hospitalization (7.7 ± 4.3 d vs 17.2 ± 17 d; P < 0.001) but no difference in postoperative complications or overall cost. CONCLUSION LH is safe and cost-effective in overweight and obese patients. Furthermore, LH is significantly associated with fewer postoperative complications and reduced hospital stay compared to OH in these patients.