Personalised blood pressure management during major noncardiac surgery and postoperative neurocognitive disorders: a randomised trial.

Background: It remains unknown whether there is a causal relationship between intraoperative hypotension and postoperative neurocognitive disorders. We tested the hypothesis that personalised-compared to routine-intraoperative blood pressure management reduces the incidence of postoperative neurocognitive disorders in patients having major noncardiac surgery. Methods: In this single-centre trial, 328 elective major noncardiac surgery patients were randomly allocated to receive personalised blood pressure management (i.e. maintaining intraoperative mean arterial pressure [MAP] above preoperative baseline MAP from automated 24-h blood pressure monitoring) or routine blood pressure management (i.e. maintaining MAP above 65 mm Hg). The primary outcome was the incidence of neurocognitive disorders (composite of delayed neurocognitive recovery and delirium) between postoperative days 3 and 7. Results: The primary outcome, neurocognitive disorders, occurred in 18 of 147 patients (12%) assigned to personalised and 21 of 148 patients (14%) assigned to routine blood pressure management (odds ratio [OR]=0.84, 95% confidence interval [CI]: 0.40-1.75, P=0.622). Delayed neurocognitive recovery occurred in 17 of 146 patients (12%) assigned to personalised and 17 of 145 patients (12%) assigned to routine blood pressure management (OR=0.99, 95% CI: 0.45-2.17, P=0.983). Delirium occurred in 2 of 157 patients (1%) assigned to personalised and 4 of 158 patients (3%) assigned to routine blood pressure management (OR=0.50, 95% CI: 0.04-3.53, P=0.684). Conclusions: Personalised intraoperative blood pressure management maintaining preoperative baseline MAP neither reduced the incidence of the composite primary outcome neurocognitive disorders between postoperative days 3 and 7 nor the incidences of the components of the composite primary outcome-delayed neurocognitive recovery and delirium-compared to routine blood pressure management in patients having major noncardiac surgery. Clinical trial registration: ClinicalTrials.gov (NCT03442907).

IL-22 promotes liver regeneration after portal vein ligation.

Background: Insufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. Methods: Liver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. Results: The remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. Conclusion: IL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

Mouse models of spontaneous liver and lung metastasis for colorectal cancer.

To investigate underlying mechanisms for cancer metastasis and promising therapies in animal models, spontaneous metastasis models can be used to recreate metastasis development. Here, we present three mouse models of spontaneous lung and/or liver metastasis induction. We describe steps for cancer cell preparation, mouse analgesia, and three injection techniques (subcutaneous, intracecal, and intramucosal). We then detail procedures for evaluating metastasis. Most of these models generate metastasis in a time span of 4 weeks in the majority of injected mice. For complete details on the use and execution of this protocol, please refer to Giannou et al.1.

IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Evidence mapping on how to perform an optimal surgical repair of large hiatal hernias.

BACKGROUND: Symptomatic and large hiatal hernia (HH) is a common disorder requiring surgical management. However, there is a lack of systematic, evidence-based recommendations summarizing recent reviews on surgical treatment of symptomatic HH. Therefore, this systematic review aimed to create evidence mapping on the key technical issues of HH repair based on the highest available evidence. METHODS: A systematic review identified studies on eight key issues of large symptomatic HH repair. The literature was screened for the highest level of evidence (LE from level 1 to 5) according to the Oxford Center for evidence-based medicine's scale. For each topic, only studies of the highest available level of evidence were considered. RESULTS: Out of the 28.783 studies matching the keyword algorithm, 47 were considered. The following recommendations could be deduced: minimally invasive surgery is the recommended approach (LE 1a); a complete hernia sac dissection should be considered (LE 3b); extensive division of short gastric vessels cannot be recommended; however, limited dissection of the most upper vessels may be helpful for a floppy fundoplication (LE 1a); vagus nerve should be preserved (LE 3b); a dorso-ventral cruroplasty is recommended (LE 1b); routine fundoplication should be considered to prevent postoperative gastroesophageal reflux (LE 2b); posterior partial fundoplication should be favored over other forms of fundoplication (LE 1a); mesh augmentation is indicated in large HH with paraesophageal involvement (LE 1a). CONCLUSION: The current evidence mapping is a reasonable instrument based on the best evidence available to guide surgeons in determining optimal symptomatic and large HH repair.

Protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies.

The transplantation model provides the opportunity to assess the relevance of a molecule of interest for tumor cell extravasation by using a respective genetically modified donor animal. Here, we present a protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies. We describe steps for animal preparation, lung transplantation, and tumor cell injection. We then detail procedures for the direct comparison of tumor cell spreading between the genetically modified left lung and the naive right lung parenchyma. For complete details on the use and execution of this protocol, please refer to Giannou et al. (2023).1.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

The Effect of Non-Alcoholic Fatty Liver Disease on Weight Loss and Resolution of Obesity-Related Disorders After Bariatric Surgery.

BACKGROUND: Patients undergoing bariatric surgery have a high incidence of non-alcoholic fatty liver disease (NAFLD). However, the effect of NAFLD or non-alcoholic steatohepatitis (NASH) on the weight loss and resolution of obesity-related disorders is a matter of debate. METHODS: In this study, we compare the long-term outcomes after bariatric with the presence of NAFLD in the liver biopsy at the time of surgery. RESULTS: The follow-up was available for 226 out of 288 patients. The mean follow-up time was 24.9 (± 13.6) months. The baseline histology showed that 112 patients (38.9%) had no NASH, 70 (24.3%) were borderline, and 106 (36.8%) had NASH. At follow-up, the mean BMI dropped from (52 ± 10.2) to (36.6 ± 8) kg/m 2. Excess weight loss (EWL) was similar in all NAFLD groups. Type 2 diabetes mellitus dropped from 35.7 to 11.4%, hypertension from 65.6 to 36.7%, hyperlipidemia from 62.3 to 33%, and obstructive sleep apnea from 37.5 to 14.9%. Only hyperlipidemia was significantly associated with NASH compared to the groups with no NASH or borderline NASH (p value = 0.002 and p value = 0.04, respectively) during the first two years of follow-up. CONCLUSION: The beneficial effects of bariatric surgery are evident across all patients with NAFLD. Patients with NASH have comparable outcomes regarding weight loss and resolution of obesity-related comorbidities.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

Lymphatic Mapping in Colon Cancer Depending on Injection Time and Tracing Agent: A Systematic Review and Meta-Analysis of Prospective Designed Studies.

An optimized lymph node yield leads to better survival in colon cancer, but extended lymphadenectomy is not associated with survival benefits. Lymphatic mapping shows several colon cancers feature aberrant drainage pathways inducing local recurrence when not resected. Currently, different protocols exist for lymphatic mapping procedures. This meta-analysis assessed which protocol has the best capacity to detect tumor-draining and possibly metastatic lymph nodes. A systematic review was conducted according to PRISMA guidelines, including prospective trials with in vivo tracer application. The risk of bias was evaluated using the QUADAS-2 tool. Traced lymph nodes, total resected lymph nodes, and aberrant drainage detection rate were analyzed. Fifty-eight studies met the inclusion criteria, of which 42 searched for aberrant drainage. While a preoperative tracer injection significantly increased the traced lymph node rates compared to intraoperative tracing (30.1% (15.4, 47.3) vs. 14.1% (11.9, 16.5), p = 0.03), no effect was shown for the tracer used (p = 0.740) or the application sites comparing submucosal and subserosal injection (22.9% (14.1, 33.1) vs. 14.3% (12.1, 16.8), p = 0.07). Preoperative tracer injection resulted in a significantly higher rate of detected aberrant lymph nodes compared to intraoperative injection (26.3% [95% CI 11.5, 44.0] vs. 2.5% [95% CI 0.8, 4.7], p < 0.001). Analyzing 112 individual patient datasets from eight studies revealed a significant impact on aberrant drainage detection for injection timing, favoring preoperative over intraoperative injection (OR 0.050 [95% CI 0.010-0.176], p < 0.001) while indocyanine green presented itself as the superior tracer (OR 0.127 [95% CI 0.018-0.528], p = 0.012). Optimized lymphatic mapping techniques result in significantly higher detection of aberrant lymphatic drainage patterns and thus enable a personalized approach to reducing local recurrence.

Sustained weight loss with semaglutide once weekly in patients without type 2 diabetes and post-bariatric treatment failure.

About 20%-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) following bariatric surgery (BS). Therefore, we aimed to retrospectively assess the effectiveness of adjunct treatment with semaglutide in patients without type 2 diabetes (T2D) with post-bariatric treatment failure over a 12 months period. Post-bariatric patients without T2D with WR or IWL (n = 29) were included in the analysis. The primary endpoint was weight loss 12 months after initiation of adjunct treatment. Secondary endpoints included change in body mass index, HbA1c, lipid profile, high sensitive C-reactive protein and liver enzymes. Total weight loss during semaglutide treatment added up to 14.7% ± 8.9% (mean ± SD, p < .001) after 12 months. Categorical weight loss was >5% in 89.7% of patients, >10% in 62.1% of patients, >15% in 34.5% of patients, >20% in 24.1% of patients and > 25% in 17.2% of patients. Adjunct treatment with semaglutide resulted in sustained weight loss regardless of sex, WR or IWL and type of surgery. Among patients with prediabetes (n = 6), 12 months treatment led to normoglycemia in all patients (p < .05). Treatment options to manage post-bariatric treatment failure are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients over a 12 months follow-up period.

TNFα aggravates detrimental effects of SARS-CoV-2 infection in the liver.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFα production. Further analysis revealed that TNFα signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFα signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time.

Abdominal emergency surgery in patients with hematological malignancies: a retrospective single-center analysis.

BACKGROUND: Hematologic patients requiring abdominal emergency surgery are considered to be a high-risk population based on disease- and treatment-related immunosuppression. However, the optimal surgical therapy and perioperative management of patients with abdominal emergency surgery in patients with coexisting hematological malignancies remain unclear. METHODS: We here report a single-center retrospective analysis aimed to investigate the impact of abdominal emergency surgery due to clinically suspected gastrointestinal perforation (group A), intestinal obstruction (group B), or acute cholecystitis (group C) on mortality and morbidity of patients with coexisting hematological malignancies. All patients included in this retrospective single-center study were identified by screening for the ICD 10 diagnostic codes for gastrointestinal perforation, intestinal obstruction, and ischemia and acute cholecystitis. In addition, a keyword search was performed in the database of all pathology reports in the given time frame. RESULTS: A total of 56 patients were included in this study. Gastrointestinal perforation and intestinal obstruction occurred in 26 and 13 patients, respectively. Of those, 21 patients received a primary gastrointestinal anastomosis, and anastomotic leakage (AL) occurred in 33.3% and resulted in an AL-related 30-day mortality rate of 80%. The only factor associated with higher rates of AL was sepsis before surgery. In patients with suspected acute cholecystitis, postoperative bleeding events requiring abdominal packing occurred in three patients and lead to overall perioperative morbidity of 17.6% and surgery-related 30-day mortality of 5.9%. CONCLUSION: In patients with known or suspected hematologic malignancies who require emergency abdominal surgery due to gastrointestinal perforation or intestinal obstruction, a temporary or permanent stoma might be preferred to a primary intestinal anastomosis.

Fatty acid-binding protein-4 (FABP4) and matrix metalloproteinase-9 (MMP9) as predictive values for nonalcoholic steatohepatitis (NASH).

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH) increases the risk for liver cirrhosis. Noninvasive tests for NAFLD/NASH exist, but they are unreliable and thus liver biopsy remains the standard for diagnosis and new noninvasive diagnostic approaches are of great interest. The aim of this study was to test whether the serum levels of fatty acid-binding protein-4 (FABP4) and matrix metalloproteinase-9 (MMP9) could be used as a diagnostic tool for NASH. METHODS: Patients who underwent bariatric surgery and simultaneous liver biopsy were identified. Biopsies were assigned a NAFLD activity score (NAS). MMP9- and FABP4- Enzyme-linked Immunosorbent Assays (ELISAs) on serum samples were performed. The serum levels of FABP4/MMP9 were compared and different models to predict NASH were developed. RESULTS: A total of 84 patients were included, 28 patients (33.3%) were diagnosed with NASH. Higher concentrations of MMP9 in NASH patients (p < 0.01) were detected. FABP4 concentrations were not significantly increased. A moderate correlation between the NAS and MMP9 concentrations (r = 0.32, P < 0.01) was observed. The neural network model fit best with the dataset, with an area under the curve (AUC) of 83% and an accuracy of 88%. CONCLUSION: Serum MMP9 levels are increased in patients with NASH and should routinely be measured in patients with obesity, but further investigations are needed to improve noninvasive NASH diagnosis.

Low-Grade Hepatic Steatosis Is Associated with Long-term Remission of Type 2 Diabetes Independent of Type of Bariatric-Metabolic Surgery.

BACKGROUND: Bariatric-metabolic surgery (BS) decreases the grade of steatosis, hepatic inflammation, and fibrosis in patients with severe obesity and non-alcoholic fatty liver disease (NAFLD). Mechanisms include substantial weight loss, but also simultaneous effects on glucose homeostasis. Therefore, we aimed to investigate the association between NAFLD and remission of type 2 diabetes (T2D) up to 8 years following different types of BS. METHODS: In a retrospective cohort study including 107 patients with obesity and T2D at baseline, the association between biopsy-proven NAFLD defined as steatosis in > 5% of hepatocytes at the time of surgery and T2D remission up to 8 years following different surgical procedures was investigated. Univariate regression analysis was used to examine the association between NAFLD and remission of T2D. RESULTS: Long-term remission of T2D was present in 56% of patients (n = 60). The presence of low-grade liver steatosis (grade 1) was associated with remission of T2D. Patients with a liver steatosis score ≥ 2 showed higher HbA1c levels at baseline. There were no significant differences in preoperative presence of lobular inflammation, hepatocyte ballooning, or fibrosis between patients who achieved T2D remission compared with those with no remission. Type of surgery did not affect remission of T2D. CONCLUSION: Our results suggest that the presence of low-grade liver steatosis is associated with remission of T2D following sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Therefore, BS should be considered at an early NAFLD stage in patients with T2D.

CD73-dependent generation of extracellular adenosine by vascular endothelial cells modulates de novo lipogenesis in adipose tissue.

Next to white and brown adipocytes present in white and brown adipose tissue (WAT, BAT), vascular endothelial cells, tissue-resident macrophages and other immune cells have important roles in maintaining adipose tissue homeostasis but also contribute to the etiology of obesity-associated chronic inflammatory metabolic diseases. In addition to hormonal signals such as insulin and norepinephrine, extracellular adenine nucleotides modulate lipid storage, fatty acid release and thermogenic responses in adipose tissues. The complex regulation of extracellular adenine nucleotides involves a network of ectoenzymes that convert ATP via ADP and AMP to adenosine. However, in WAT and BAT the processing of extracellular adenine nucleotides and its relevance for intercellular communications are still largely unknown. Based on our observations that in adipose tissues the adenosine-generating enzyme CD73 is mainly expressed by vascular endothelial cells, we studied glucose and lipid handling, energy expenditure and adaptive thermogenesis in mice lacking endothelial CD73 housed at different ambient temperatures. Under conditions of thermogenic activation, CD73 expressed by endothelial cells is dispensable for the expression of thermogenic genes as well as energy expenditure. Notably, thermoneutral housing leading to a state of low energy expenditure and lipid accumulation in adipose tissues resulted in enhanced glucose uptake into WAT of endothelial CD73-deficient mice. This effect was associated with elevated expression levels of de novo lipogenesis genes. Mechanistic studies provide evidence that extracellular adenosine is imported into adipocytes and converted to AMP by adenosine kinase. Subsequently, activation of the AMP kinase lowers the expression of de novo lipogenesis genes, most likely via inactivation of the transcription factor carbohydrate response element binding protein (ChREBP). In conclusion, this study demonstrates that endothelial-derived extracellular adenosine generated via the ectoenzyme CD73 is a paracrine factor shaping lipid metabolism in WAT.

The impact of nitroglycerine and volume on gastric tube microperfusion assessed by indocyanine green fluorescence imaging.

The influence of hypervolemia and intraoperative administration of nitroglycerine on gastric tube microperfusion remains unclear The present study aimed to investigate the impact of different hemodynamic settings on gastric tube microperfusion quantified by fluorescence imaging with Indocyanine green (ICG-FI) as a promising tool for perfusion evaluation. Three groups with seven pigs each were formed using noradrenaline, nitroglycerin, and hypervolemia for hemodynamic management, respectively. ICG-FI, hemodynamic parameters, and transit-time flow measurement (TTFM) in the right gastroepiploic artery were continuously assessed. Fluorescent microspheres (FM) were administered, and the partial pressure of tissue oxygen was quantified. The administration of nitroglycerine and hypervolemia were both associated with significantly impaired microperfusion compared to the noradrenaline group quantified by ICG-FI. Even the most minor differences in microperfusion could be sufficiently predicted which, however, could not be represented by the mean arterial pressure measurement. Histopathological findings supported these results with a higher degree of epithelial damage in areas with impaired perfusion. The values measured by ICG-FI significantly correlated with the FM measurement. Using tissue oxygenation and TTFM for perfusion measurement, changes in microperfusion could not be comprehended. Our results support current clinical practice with restrictive volume and catecholamine administration in major surgery. Hypervolemia and continuous administration of nitroglycerine should be avoided.

A Critical Role of the IL-22-IL-22 Binding Protein Axis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22-IL-22BP axis in HCC.

Quantification of gastric tube perfusion following esophagectomy using fluorescence imaging with indocyanine green.

INTRODUCTION: Anastomotic leakage (AL) remains a prevalent and life-threatening complication after esophagectomy. Gastric tube perfusion assessment using indocyanine green fluorescence imaging (ICG-FI) has been published in several studies and appears to be a promising tool to reduce AL rates by changing the surgical approach, namely by an intraoperative evaluation of the anastomosis localization. METHODS: In this study, gastric tube perfusion was quantified by using ICG-FI in 20 high-risk patients undergoing esophagectomy. From a time-dependent fluorescence intensity curve, the following three parameters were evaluated: slope of fluorescence intensity (SFI), background subtracted peak fluorescence intensity (BSFI), and time to slope (TTS). RESULTS: The values between pyloric region and tip showed a similar downward trend and SFI and BSFI significantly correlated with the distance to the pyloric region. SFI and BSFI were significantly decreased at the tip of the gastric tube. The placement of anastomosis in an area with homogenous fluorescence pattern was correlated with no AL in 92.9% of cases. An inhomogeneous fluorescence pattern at anastomotic site was a risk factor for the occurrence of an AL (p < 0.05). Reduction of perfusion up to 32% using SFI and up to 23% using BSFI was not associated with AL. CONCLUSION: ICG-FI can be used to quantify the gastric tube perfusion by calculating SFI, BSFI, and TTS. The anastomosis should be created in areas with homogeneous fluorescence pattern. A reduction in blood flow of up to 32% can be accepted without causing an increased rate of insufficiency.

Comparison of Anti-factor Xa Levels in Female and Male Patients with Obesity After Enoxaparin Application for Thromboprophylaxis.

PURPOSE: Venous thromboembolic events (VTEs) are common complications after bariatric surgery, and enoxaparin is commonly used to prevent VTEs. The risk for VTEs is sex-specific. Whether enoxaparin application results in similar anti-factor Xa activities (aFXa) in males and females with obesity remains to be determined. We investigated whether our dosage regimen of enoxaparin resulted in similar serum aFXa levels in female and male patients undergoing bariatric surgery. MATERIALS AND METHODS: We administered enoxaparin twice daily in patients undergoing bariatric surgery. Patients with a body mass index (BMI) > 60 kg/m2 (n = 11) received 60 mg enoxaparin (group 2), and patients with lower BMI (n = 86) received 40 mg per dose (group 1). Peak aFXa levels were measured 3 days after surgery. The primary outcome was the aFXa level. As a secondary outcome, we detected VTEs and major bleeding events and explored the possible influencing factors of aFXa. RESULTS: Women had higher aFXa than men, but after matching for anthropometric values, the two groups were similar (females: 0.17 ± 0.08 U/ml; males: 0.18 ± 0.08 U/ml). Linear regression revealed a moderate relationship between weight and aFXa levels. The 3-month follow-up was attended by 94.9%, at which one patient had pulmonary embolism. CONCLUSION: Individual enoxaparin dosage regimens for men and women do not seem to be required. Weight-based dosing regimen seems to be a more reasonable choice.