Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

Brown adipose tissue (BAT) dissipates energy1,2 and promotes cardiometabolic health3. Loss of BAT during obesity and ageing is a principal hurdle for BAT-centred obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. This apoptotic secretome enhances expression of the thermogenic programme in healthy adipocytes. This effect is mediated by the purine inosine that stimulates energy expenditure in brown adipocytes by the cyclic adenosine monophosphate-protein kinase A signalling pathway. Treatment of mice with inosine increased BAT-dependent energy expenditure and induced 'browning' of white adipose tissue. Mechanistically, the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) regulates inosine levels in BAT: ENT1-deficiency increases extracellular inosine levels and consequently enhances thermogenic adipocyte differentiation. In mice, pharmacological inhibition of ENT1 as well as global and adipose-specific ablation enhanced BAT activity and counteracted diet-induced obesity, respectively. In human brown adipocytes, knockdown or blockade of ENT1 increased extracellular inosine, which enhanced thermogenic capacity. Conversely, high ENT1 levels correlated with lower expression of the thermogenic marker UCP1 in human adipose tissues. Finally, the Ile216Thr loss of function mutation in human ENT1 was associated with significantly lower body mass index and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with a 'replace me' signalling function that regulates thermogenic fat and counteracts obesity.

Perioperative therapy with FLOT4 significantly increases survival in patients with gastroesophageal and gastric cancer in a large real-world cohort.

In 2019, the FLOT4 protocol was established as the new standard for perioperative therapy in patients with locally advanced gastroesophageal and gastric cancer. Whether this protocol is beneficial in a real-world setting remains a question with limited answers to date. In our study, a large cohort of unselected patients treated with FLOT4 was analyzed and compared to protocols based on 5-FU/platinum derivative. This retrospective analysis included patients with locally advanced gastroesophageal and gastric cancer treated with perioperative FLOT or 5-FU/platinum derivative at University Hospital, Bonn between 2010 and 2022 in a curative setting (n = 99). Overall survival, disease-free survival, therapy response and therapy complications were analyzed. Patients treated with FLOT showed a statistically significant longer median overall survival of 57.8 vs 28.9 months (HR: 0.554, 95% CI: 0.317-0.969, P = .036). Moreover, pathological tumor regression (pTR) was significantly higher in the FLOT group compared to the 5-FU/platinum group (P = .001). Subgroup analysis showed a favorable survival benefit for the FLOT vs 5-FU/platinum derivate in patients with AEG and non-signet cell carcinoma. Overall, FLOT was tolerated well but CTCAE ≥3 grade neutropenia and diarrhea occurred more often within the FLOT group. Similar to the prospective phase II/III trials, FLOT4 was the best protocol for patients with locally advanced gastroesophageal and gastric cancer as perioperative therapy in terms of overall survival and pathological response rate compared to 5-FU/platinum derivative protocols. Interestingly, patients with gastroesophageal cancer benefitted more from this therapy. In contrast, patients with signet ring cells appear not to benefit from addition of docetaxel.

Sinusoidal obstruction syndrome in the animal model: influence on liver surgery.

PURPOSE: In recent years, multimodal treatment approaches have led to an increased median survival time of patients with colorectal liver metastases. In particular, this results from new perioperative chemotherapy regimens, which in turn are accompanied by an increased risk of perioperative bleeding and/or liver failure due to the hepatotoxic side effects. Nineteen to 58 % of patients treated with oxaliplatin develop sinusoidal obstruction syndrome (SOS). The influence of preexisting SOS on liver surgery remains controversial. METHODS: Animals were operated 4 days after SOS induction with monocrotaline and received either vascular occlusion in the form of Pringle maneuver (PM) or hepatectomy (LR; 70 %) or a combination of both (LR + PM). Postoperative liver function was assessed by determination of liver enzyme levels, bile production, and tissue oxygen saturation. RESULTS: Preexisting SOS impaired morbidity after liver resection, reflected by elevated liver enzyme levels, reduced bile secretion, and low liver tissue oxygenation levels. Mortality was increased by up to 25 %. Additional ischemia in the form of PM showed no further impact in the LR ± PM group compared to LR alone. CONCLUSION: PM without LR results in high enzyme distribution in the SOS group. SOS significantly affects the outcome after liver resection in our experimental rat model only without PM and showed no protective effect in ischemia in the form of PM.

[Prognostic Factors of Open Abdomen Treatment in Visceral Surgery]. / Prognosefaktoren der offenen Abdominalbehandlung in der Viszeralchirurgie.

Introduction In general surgery, open abdomen treatment (OAT) is used to treat abdominal compartment syndrome (ACS) and sepsis, often after a primary surgical procedure associated with complications. The results achieved in this patient population may depend on factors that are yet unknown. This study evaluates independent patient-related prognostic factors after OAT. Methods 38 clinical parameters and survival data of 165 consecutive general surgery patients after OAT were entered into a prospective database according to a defined algorithm in order to analyse the underlying surgical pathology, predictors of survival and important aspects of OAT-related morbidity. Independent predictors of survival, OAT-related morbidity and duration of hospital stay were identified. Results Common indications for OAT were peritonitis, haemorrhage and ACS. Median age was 60 years and > 80 % of patients were ASA III/IV; median follow-up was 23 months. Oncologic surgery was performed in 19 % of cases. 30-day and 1-year mortality was 11 % and 34 %, respectively. Malignancy was a negative predictor (OR: 4.63, 95 % CI: 2.00-10.7) while mild obesity (BMI 25-35) and primary fascial closure, which was achieved in 82 % of patients, improved survival (OR: 0.2, 95 % CI: 0.07-0.55; OR: 0.19, 95 % CI: 0.06-0.57). Enteroatmospheric fistula (EAF) and giant hernia with impossible fascial closure were frequent after OAT (19 and 18 %), and malignancy was an independent risk factor for EAF (OR 3.47, CI [95 %]: 1.41-8.53). Vacuum-assisted wound closure or polyglactin mesh interposition did not affect EAF incidence. Conclusions General surgery patients after OAT differ significantly from trauma patients, and mortality as well as long-term morbidity is high. Outcome is greatly determined by independent patient-related factors after OAT. A tailored surgical approach based on objective evidence is needed to further improve the results after OAT.

Efficacy and tolerability of fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in unselected patients with advanced gastric and gastroesophageal cancer: does age really matter?

PURPOSE: Fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) regimen has shown strong efficacy as perioperative therapy for patients with locally advanced gastric (GC) and gastroesophageal (AEG) carcinoma. In the palliative situation, FLOT is recommended only for young fit patients. Data of efficacy and tolerability of FLOT in elderly patients are scarce and controversial. Thus, this study aimed to provide real-life experience of elderly patients with GC and AEG treated with FLOT as first-line palliative chemotherapy. METHODS: Patients with advanced or metastatic GC or AEG and treated with FLOT as first-line palliative therapy between 2010 and 2021 were analyzed. Patients were grouped into < 65 years old (n = 35) and ≥ 65 years old (n = 22) groups. Overall survival (OS), progression-free survival (PFS), feasibility and toxicity were analyzed. RESULTS: The median OS was 10.4 months with no significant difference between both groups (HR 0.86; 95% CI 0.48, 1.57; p = 0.632). The ECOG performance status showed powerful influence on OS in the subgroup analysis with median OS of 12.3 months for ECOG = 0 compared to 5.0 months for ECOG ≥ 1 (p = 0.015) as well as in multivariate analysis (HR 2.62; 95% CI 1.36, 5.04; p = 0.004). CONCLUSION: In the present study the ECOG performance status showed a stronger prognostic value than patient age in FLOT as first- line therapy in a real-life cohort with advanced and metastatic GC and AEG. The performance status should therefore be considered in the therapeutic decision making of elderly patients with GC and AEG.

Spatial patterns and temporal variations of traffic-related air pollutants and estimating its health effects in Isfahan city, Iran.

Isfahan as an important industrial city has faced with air pollution recently. Thus, we assessed the spatial and temporal trends of ambient PM2.5, CO, SO2, and O3 and for estimating their health effect on Isfahan citizens between March 2018 and March 2019 through the AirQ+ software. Our results showed that citizens of Isfahan in almost 240, 167, and 134 of the days in the year has exposure to PM2.5, SO2, and O3 higher than the WHO daily guideline, respectively. Daily variations of PM2.5, CO, and SO2 concentration showed the increasing trend of pollutants in the morning to evening. The maximum concentrations of O3 were observed in the noonday. Also, the concentrations of these pollutants on Friday due to the holiday effect were higher than the weekdays. Except for O3, the PM2.5, CO, and SO2 concentrations in the cold months and cold seasons was higher compared with the hot months and hot seasons. The total number of deaths because of lung cancer, natural mortality, ischemic heart disease, chronic obstructive pulmonary disease,, stroke associated with ambient PM2.5 with the attributable proportion (AP) 11.43%, 11.63%, 15.96%, 15.15%, and 13.1% (95% CI) were 683, 19, 2, 202, and 55 cases, respectively. Therefore, the present study provides additional data for the provincial managers and politicians useful in planning proper strategies of air pollution control to decrease exposure and attributable mortalities.

A Combined TLR7/TLR9/GATA3 Score Can Predict Prognosis in Biliary Tract Cancer.

Biliary tract cancer (BTC) refers to a heterogenous group of epithelial malignancies arising along the biliary tree. The highly aggressive nature combined with its silent presentation contribute to the dismal prognosis of this tumor. Tumor-infiltrating immune cells (TIICs) are frequently present in BTC and there is growing evidence regarding their role as therapeutic targets. In this study, we analyzed the immune cell infiltration in BTC and developed a promising immune signature score to predict prognosis in BTC. Immunohistochemistry (IHC) was carried out on tissue microarray sections from 45 patients with resectable cholangiocarcinoma for the detection of 6-sulfoLacNAc+ monocytes (slanMo), BDCA-2+ plasmacytoid dendritic cells (pDC), CD8+ or CD4+T-lymphocytes, CD103+ cells, GATA3+ cells, Toll-like receptor (TLR) 3, 7 and 9-expressing cells as well as programmed cell death protein 1 and programmed cell death ligand 1 positive cells. Data from the IHC staining were analyzed and correlated with clinicopathological and survival data. High expression of TLR7, TLR9, and GATA3 was associated with improved overall survival (OS, Log-rank p < 0.05). In addition, TLR9 was associated with better disease-free survival (Log-rank p < 0.05). In the multivariate Cox proportional-hazards model for OS, the TLR/TLR9/GATA3 score was found to be an independent prognostic factor for OS ("Score 2" vs. "Score 0": HR 11.17 95% CI 2.27-54.95, p < 0.01).

Bevacizumab exacerbates sinusoidal obstruction syndrome (SOS) in the animal model and increases MMP 9 production.

BACKGROUND: Thanks to modern multimodal treatment the ouctome of patients with colorectal cancer has experienced significant improvements. As a downside, agent specific side effects have been observed such as sinusoidal obstruction syndrome (SOS) after oxaliplatin chemotherapy (OX). Bevazicumab targeting VEGF is nowadays comprehensively used in combination protocols with OX but its impact on hepatotoxicity is thus far elusive and focus of the present study. RESULTS: After MCT administration 67% of animals developed SOS. GOT serum concentration significantly increased in animals developing SOS (p < 0.001). Subsequent to MCT administration 100% of animals treated with Anti-VEGF developed SOS. In contrast, animals receiving VEGF developed SOS merely in 40% while increasing the VEGF dose led to a further decrease in SOS development to 25%. MMP 9 concentration in animals developing SOS was significantly higher compared to controls (p < 0,001). Additional treatment with Anti-VEGF increased the MMP 9 concentration significantly (p < 0,05). CONCLUSIONS: Preservation of liver function is a central goal in both curative and palliative treatment phases of patients with CRC. Thus, knowledge about hepatotoxic side effects of chemotherapeutic and biological agents is crucial. From the results it can be concluded that Anti-VEGF exacerbates SOS paralleled by MMP 9 production. Therefore, OX-Bevacizumab combination therapies should be administered with caution, especially if liver parenchyma damage is apparent. METHODS: Male Sprague-Dawley rats were gavaged Monocrotaline (MCT) to induce SOS. Recombinant VEGF or an Anti-VEGF antibody was administered to MCT-treated rats and the hepatotoxic effect monitored in defined time intervals. MMP 9 expression in the liver was measured by ELISA.

Donor liver quality after hypovolemic shock and venous systemic oxygen persufflation in an experimental animal model.

BACKGROUND: The ever growing demand for liver transplantation inevitably necessitates an expansion of the donor pool. Utilization of "shock organs" is considered suboptimal to date while the associated outcome has hardly been investigated. MATERIALS AND METHODS: Male Wistar rats underwent a period of 30 min of hypovolemic shock. After 24 h livers were explanted and prior to reperfusion underwent either 18 h of cold storage (CS; N = 6) or 17 h of CS followed by 60 min venous systemic oxygen persufflation (VSOP; N = 6). The outcome of "shock organs (SHBD)" was compared to heart-beating donor (HBD; N = 12) as positive control and non-heart-beating donor (NHBD; N = 12) as negative control animal groups. Liver function was assessed by measuring enzyme release (AST, ALT, LDH), bile production, portal vein pressure and hepatic oxygen uptake during reperfusion. For reperfusion, the isolated perfused rat liver system was used. RESULTS: Liver function was severely limited in NHBD group compared to HBD organs after 18 h of CS (e.g., AST; HBD: 32.25 ± 7.25 U/l vs. NHBD: 790 ± 414.56 U/l; p < 0.005). VSOP improved liver function of NHBD organs significantly (AST; NHBD + VSOP: 333.6 ± 149.1 U/l; p < 0.005). SHBD organs showed a comparable outcome to HBD and clearly better results than NHBD organs after 18 h of CS (AST; SHBD: 76.4 ± 21.9 U/l). After 17 h of CS accompanied by 60 min VSOP, no improvement concerning liver function and integrity of SHBD organs was observed while the results were severely deteriorated by VSOP resulting in higher enzyme release (AST; SHBD + VSOP: 213 ± 61 U/l, p < 0.001), higher portal vein pressure (SHBD: 10.8 ± 1.92 mm Hg vs. SHBD + VSOP: 21.6 ± 8.8 mm Hg; p < 0.05) and lower hepatic oxygen uptake (SHBD: 321.75 ± 3.87 ml/glw/min vs. SHBD + VSOP: 395.8 ± 46.64 ml/glw/min, p < 0.05) at 24 h. CONCLUSIONS: Our data suggest that the potential of "shock organs" within liver transplantation may be underestimated. If our findings are reproducable in humans, SHBD grafts should be considered as a valuable source for expanding the thus far limited donor pool.

An Improved Suture Technique for Perform Biliary Reconstruction in Orthotopic Liver Transplantation.

BACKGROUND: The biliary anastomosis remains to be the Achilles' heel of liver transplantation. The incidence of biliary complications (e.g., stenosis and leakage) is immanent and the optimal type of reconstruction is unclear. The aim of this study was to compare 2 different bile duct suture techniques regarding their benefits in the prevention of biliary complications. MATERIAL AND METHODS: From 1992 to 2012, the transplanted patients (n=394) of our center were analyzed retrospectively in terms of suture techniques and consecutive biliary complications. Secondary, possible risk factors (cold ischemic time, donor age, and preoperative liver function) were examined. An end-to-end choledocho-choledochostomy without T-tube was performed during orthotopic liver transplantation whenever possible. In group 1 (n=123) the biliary reconstruction was performed completely by continuous-suture technique. In group 2 (n=164) continuous-suture technique was also performed in posterior wall of the bile duct, but the anterior wall was closed by interrupted-suture technique. RESULTS: The overall biliary complication rate was 19.6%. There were no significant differences in biliary complications between the groups. Analysis of risk factors showed no influence on the complication rate. CONCLUSIONS: The argument for the interrupted-suture technique is a better overview and a lower risk to grab the posterior wall during the anastomotic realization. The threads of the anterior wall can be presented individually and then be knotted.

Malignant melanoma of the ileo-anal pouch anastomosis after restorative proctocolectomy for ulcerative colitis: report of a case.

A 62 year-old patient with therapy-refractory pouchitis after proctocolectomy for ulcerative colitis was admitted with hematochezia and abdominal discomfort. A malignant melanoma (MM) was found after repeated biopsies of the pouch. Complete staging revealed no evidence for distant metastases and the patient underwent abdominoperineal pouch resection. Six weeks later, the patient was readmitted because of severe general deterioration and diffuse metastatic spread to the liver was found. The patient died of hepatorenal syndrome shortly thereafter.Patients with inflammatory bowel disease are at increased risk of developing cancer, including rarities such as MM. Our experience stresses the importance of repeated biopsies in therapy-refractory pouchitis.