Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes

believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients’ samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app

The Clavien-Dindo Classification in Pancreatic Surgery: A Clinical and Economic Validation

Background/Aims: In 2004 P. A. Clavien and D. Dindo published the well-known grading system of postoperative complications. It is established in several surgical disciplines. The aim of this study was to assess its validity in pancreatic surgery. The impact of complication grade on economic resources was investigated as well. Methods: From a prospective database, we retrospectively evaluated all patients who underwent pancreatic resection between January 2009 and December 2014 at our department. 309 patients received pancreatic head resection (pylorus-preserving pancreatoduodenectomy (PPPD) or Kausch-Whipple), total pancreatectomy or left resection. We performed a univariate analysis of the correlation between the Clavien-Dindo classification-grade (CDC-grade) with length of postoperative stay (LOS) and DRG-related (diagnosis related groups) remuneration using Kruskal-Wallis test. Furthermore, we performed a subgroup analysis (chi-square test and Fishers-test) of demographic, clinical, and perioperative data. Results: American Society of Anesthesiologists (ASA) score (p = 0.0014), operation time (p = 0.0229) and intraoperative blood loss (p = 0.0016) showed significant correlation with CDC-grade. Increasing LOS and DRG-related remuneration correlated significantly with increasing CDC-grade (p < 0.0001). Conclusion: The CDC-grading system shows high correlation to clinical outcome and case-related remuneration in pancreatic surgery. Therefore, it is a valid tool for evaluation and comparison of surgical techniques and surgical centers

Stereotactic Body Radiation Therapy versus Surgical Resection for Stage I/II Hepatocellular Carcinoma

SBRT is an emerging locoregional treatment modality for hepatocellular carcinoma (HCC). Although local tumor control rates seem encouraging, large-scale survival data comparing SBRT to surgical resection are lacking. We identified patients with stage I/II HCC from the National Cancer Database amenable for potential surgical resection. Patients undergoing hepatectomy were matched by propensity score (1:2) with patients who underwent SBRT as primary treatment. A total of 3787 (91%) and 366 (9%) patients underwent surgical resection or SBRT between 2004 and 2015, respectively. After propensity matching, the 5-year overall survival was 24% (95% CI 19–30%) in the SBRT group versus 48% (95% CI 43–53%) in the surgery group (p p < 0.001). Surgical resection may be associated with prolonged overall survival compared with SBRT in patients with stage I/II HCC

Infrahepatic Inferior Vena Cava Clamping does not Increase the Risk of Pulmonary Embolism Following Hepatic Resection

Background!#!Infrahepatic inferior vena cava (IVC) clamping reduces central venous pressure. However, controversies remain regarding its impact on postoperative complications, particularly, the incidence of postoperative pulmonary embolism (PE). The aim of the study was to determine the impact of IVC clamping on the incidence of PE in patients undergoing hepatectomy.!##!Methods!#!A pooled analysis of five prospective trials on patients who underwent hepatic resection over a period of 10 years was performed. Patients with infrahepatic IVC clamping were compared to patients without infrahepatic IVC clamping. Outcomes were studied by univariate and multivariate analyses.!##!Results!#!Of 505 included patients, 141 patients had IVC clamping and 364 patients served as control group. The rate of postoperative PE was comparable between groups (3% vs. 3%; P = 0.762), as were postoperative morbidity (P = 0.932), bile leakage (P = 0.272), posthepatectomy hemorrhage (P = 0.095), and posthepatectomy liver failure (P = 0.605), respectively. No clinicopathological and intraoperative risk factors were found to predict the onset of PE. Subgroup analyses of patients with major hepatectomy and vascular resections confirmed no adverse perioperative outcomes to be associated with IVC clamping.!##!Conclusions!#!Infrahepatic IVC clamping does not increase the incidence of postoperative PE

Role of Albumin as a Nutritional and Prognostic Marker in Elective Intestinal Surgery

Background. The aim of this study was to investigate albumin, nutritional status, and inflammation in the perioperative course of patients undergoing elective intestinal surgery. Methods. A retrospective analysis of patients with preoperative measurements of nutritional parameters who underwent intestinal surgery between April 2017 and August 2018 at our institution was performed. Preoperatively, the correlation of albumin levels with markers for inflammation and nutritional status was investigated. Postoperatively, albumin levels were assessed with regard to high-grade morbidity and inflammation. Results. A total of 105 patients were included. Preoperatively, albumin levels were correlated with both markers for nutritional status and inflammation, with phase angle (PA) (p=0.004) and C-reactive protein (CRP) (p<0.001) as independent factors predicting the albumin levels in multivariable analysis. Postoperatively, the reduction in serum albumin (∆-albumin) on postoperative day (POD) 1/2 (p=0.025) and POD 4/5 (p=0.003) was significantly associated with Clavien–Dindo complications ≥grade III. A cut-off value of 27.3% for ∆-albumin on POD 1/2 predicted postoperative high-grade morbidity (sensitivity 75% and specificity 69%). The product of ∆-albumin and CRP on POD 4/5 identified patients with major complications more reliably than ∆-albumin or CRP alone (sensitivity 91% and specificity 72%). Conclusion. Preoperatively, albumin was a marker for nutritional status even if an inflammatory component was present. Postoperatively, ∆-albumin on POD 1/2 predicted high-grade morbidity. A new marker to identify patients with major complications on POD 4/5 is presented

Clinical pathways for oncological gastrectomy: are they a suitable instrument for process standardization to improve process and outcome quality for patients undergoing gastrectomy? A retrospective cohort study

(1) Background: Oncological gastrectomy requires complex multidisciplinary management. Clinical pathways (CPs) can potentially facilitate this task, but evidence related to their use in managing oncological gastrectomy is limited. This study evaluated the effect of a CP for oncological gastrectomy on process and outcome quality. (2) Methods: Consecutive patients undergoing oncological gastrectomy before (n = 64) or after (n = 62) the introduction of a CP were evaluated. Assessed parameters included catheter and drain management, postoperative mobilization, resumption of diet and length of stay. Morbidity, mortality, reoperation and readmission rates were used as indicators of outcome quality. (3) Results: Enteral nutrition was initiated significantly earlier after CP implementation (5.0 vs. 7.0 days, p < 0.0001). Readmission was more frequent before CP implementation (7.8% vs. 0.0%, p = 0.05). Incentive spirometer usage increased following CP implementation (100% vs. 90.6%, p = 0.11). Mortality, morbidity and reoperation rates remained unchanged. (4) Conclusions: After implementation of an oncological gastrectomy CP, process quality improved, while indicators of outcome quality such as mortality and reoperation rates remained unchanged. CPs are a promising tool to standardize perioperative care for oncological gastrectom

Contralateral Liver Hypertrophy and Oncological Outcome Following Radioembolization with 90Y-Microspheres: A Systematic Review

Radioembolization with 90Y-microspheres has been reported to induce contralateral liver hypertrophy with simultaneous ipsilateral control of tumor growth. The aim of the present systematic review was to summarize the evidence of contralateral liver hypertrophy and oncological outcome following unilateral treatment with radioembolization. A systematic literature search using the MEDLINE, EMBASE, and Cochrane libraries for studies published between 2008 and 2020 was performed. A total of 16 studies, comprising 602 patients, were included. The median kinetic growth rate per week of the contralateral liver lobe was 0.7% and declined slightly over time. The local tumor control was 84%. Surgical resection after radioembolization was carried out in 109 out of 362 patients (30%). Although the available data suggest that radioembolization prior to major hepatectomy is safe with a promising oncological outcome, the definitive role of radioembolization requires assessment within controlled clinical trials

Human ILC3 Exert TRAIL-Mediated Cytotoxicity Towards Cancer Cells

Group 3 helper Innate Lymphoid Cells (ILC3s) are cytokine-producing lymphocytes that respond to stress signals released during disturbed tissue homeostasis and infection. Upon activation, ILC3s secrete IL-22 and IL-17, and orchestrate immune responses against extracellular pathogens. Their role in cancer remains poorly explored. To determine their anti-cancer effector potential, we co-cultured cytokine-activated human ILC3s with cancer cells of different origins. ILC3s were able to directly respond to tumor cells, resulting in enhanced IFN-γ production. Upon tumor cell encounter, ILC3s maintained expression of the transcription factor RORγt, indicating that ILC3s preserved their identity. ILC3s were able to directly kill both hepatocellular carcinoma and melanoma tumor cells expressing cell-death receptor TRAILR2, through the activation of Caspase-8 in target cells. Moreover, liver-derived cytokine-activated ILC3s also expressed TRAIL and were able to eliminate hepatoblastoma cells. Together, our data reveal that ILC3s can participate in anti-tumor immune response through direct recognition of tumor cells resulting in IFN-γ release and TRAIL-dependent cytotoxicity. Thus, ILC3s might be ancillary players of anti-tumor immunity in tissues, acting as primary responders against transformed or metastasizing cells, which might be further exploited for therapies against cancer