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

Close negative correlation of local and circulating Dickkopf-1 and Sclerostin levels during human fracture healing

Abstract Wnt signaling is critically involved in fracture healing. Existing data predominantly relies on rodent models. Here, we explored local and circulating Dickkopf-1 (DKK1) levels in patients with respect to fracture healing and explore its association to sclerostin (SOST). 69 patients after surgical stabilization of long bone fractures of which six patients had impaired fracture healing were included in this study. Life-style and patient related factors with a known effect on DKK1 and SOST were recorded. DKK1 and SOST concentrations were measured using enzyme-linked immunosorbent assay (ELISA) at the fracture site and in circulation. DKK1 and SOST showed a close inverse correlation. In fracture hematoma and immediately after trauma DKK1 levels were significantly reduced while SOST levels were significantly increased, compared to healthy control. Postoperatively, DKK1 peaked at week 2 and SOST at week 8, again demonstrating a close negative correlation. Age and smoking status affected the balance of DKK1 and SOST, while type 2 diabetes and sex did not demonstrate a significant influence. Early postoperative elevation of SOST without compensatory DKK1 decrease was associated with fracture non-union in younger patients (< 50a). The close inverse correlation and very rapid dynamics of DKK1 and SOST locally as well as systemically suggest their critical involvement during human fracture healing. Importantly, as immediate compensatory feedback mechanism are apparent, we provide evidence that dual-blockade of DKK1 and SOST could be critical to allow for therapeutic efficiency of Wnt targeted therapies for fracture healing

Current evidence on posthepatectomy liver failure: comprehensive review

Introduction: Despite important advances in many areas of hepatobiliary surgical practice during the past decades, posthepatectomy liver failure (PHLF) still represents an important clinical challenge for the hepatobiliary surgeon. The aim of this review is to present the current body of evidence regarding different aspects of PHLF. Methods: A literature review was conducted to identify relevant articles for each topic of PHLF covered in this review. The literature search was performed using Medical Subject Heading terms on PubMed for articles on PHLF in English until May 2022. Results: Uniform reporting on PHLF is lacking due to the use of various definitions in the literature. There is no consensus on optimal preoperative assessment before major hepatectomy to avoid PHLF, although many try to estimate future liver remnant function. Once PHLF occurs, there is still no effective treatment, except liver transplantation, where the reported experience is limited. Discussion: Strict adherence to one definition is advised when reporting data on PHLF. The use of the International Study Group of Liver Surgery criteria of PHLF is recommended. There is still no widespread established method for future liver remnant function assessment. Liver transplantation is currently the only effective way to treat severe, intractable PHLF, but for many indications, this treatment is not available in most countries

Current evidence on posthepatectomy liver failure: comprehensive review

Introduction: Despite important advances in many areas of hepatobiliary surgical practice during the past decades, posthepatectomy liver failure (PHLF) still represents an important clinical challenge for the hepatobiliary surgeon. The aim of this review is to present the current body of evidence regarding different aspects of PHLF. Methods: A literature review was conducted to identify relevant articles for each topic of PHLF covered in this review. The literature search was performed using Medical Subject Heading terms on PubMed for articles on PHLF in English until May 2022. Results: Uniform reporting on PHLF is lacking due to the use of various definitions in the literature. There is no consensus on optimal preoperative assessment before major hepatectomy to avoid PHLF, although many try to estimate future liver remnant function. Once PHLF occurs, there is still no effective treatment, except liver transplantation, where the reported experience is limited. Discussion: Strict adherence to one definition is advised when reporting data on PHLF. The use of the International Study Group of Liver Surgery criteria of PHLF is recommended. There is still no widespread established method for future liver remnant function assessment. Liver transplantation is currently the only effective way to treat severe, intractable PHLF, but for many indications, this treatment is not available in most countries

The Ratio of Activin A and Follistatin-Like 3 Is Associated With Posthepatectomy Liver Failure and Morbidity in Patients Undergoing Liver Resection

Background and Aims: Activin A is a key regulator in liver regeneration, but data evaluating its role in humans after hepatic surgery are limited. In this study we explore the predictive role of circulating activin A, its antagonist follistatin-like 3 (FSTL-3), and their ratio for posthepatectomy liver failure (PHLF) and monitor their levels after surgery, to evaluate their role in human liver regeneration. Methods: Activin A and FSTL-3 levels were assessed in 59 patients undergoing liver surgery. Using receiver operating characteristic analysis, we evaluated the predictive potential of activin A, FSTL-3, and their ratio. Results: While perioperative dynamics of activin A and FSTL3 were significantly affected by hepatic resection (activin A P = .045, FSTL-3 P = .005), their functionally relevant ratio did not significantly change (P = .528). Neither activin A nor FSTL-3 alone but only their ratio exhibited a significant predictive potential for PHLF (area under the curve: 0.789, P = .038). Patients with low preoperative activin A/FSTL-3 ratio were found to more frequently suffer from PHLF (0.017) and morbidity (0.005). Conclusion: Activin A/FSTL-3 ratio predicts PHLF and morbidity. Its significance in preoperative patient assessment needs to be further validated in larger, independent cohorts

Glucagon-like peptide-1 and glucagon-like peptide-2 regulation during human liver regeneration

Abstract Accumulating evidence suggests that metabolic demands of the regenerating liver are met via lipid metabolism and critical regulators of this process. As such, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) critically affect hepatic regeneration in rodent models. The present study aimed to evaluate potential alterations and dynamics of circulating GLP-1 and GLP-2 in patients undergoing liver resections, focusing on post-hepatectomy liver failure (PHLF). GLP-1, GLP-2, Interleukin-6 (IL-6) and parameters of lipid metabolism were determined perioperatively in fasting plasma of 46 patients, who underwent liver resection. GLP-1 and GLP-2 demonstrated a rapid and consistently inverse time course during hepatic regeneration with a significant decrease of GLP-1 and increase of GLP-2 on POD1. Importantly, these postoperative dynamics were significantly more pronounced when PHLF occurred. Of note, the extent of resection or development of complications were not associated with these alterations. IL-6 mirrored the time course of GLP-2. Assessing the main degradation protein dipeptidyl peptidase 4 (DPP4) no significant association with either GLP-1 or -2 could be found. Additionally, in PHLF distinct postoperative declines in plasma lipid parameters were present and correlated with GLP-2 dynamics. Our data suggest dynamic inverse regulation of GLP-1 and GLP-2 during liver regeneration, rather caused by an increase in expression/release than by changes in degradation capacity and might be associated with inflammatory responses. Their close association with circulating markers of lipid metabolism and insufficient hepatic regeneration after liver surgery suggest a critical involvement during these processes in humans

Perioperative Chemotherapy Including Bevacizumab in Potentially Curable Metastatic Colorectal Cancer: Long-Term Follow-Up of the ASSO-LM1 Trial

In 2007, the ASSO-LM1 trial, a multicenter prospective study, was initiated to investigate the resectability (R0) rate following preoperative combination therapy with XELOX and bevacizumab in patients with potentially resectable colorectal liver metastases. Six cycles of systemic therapy were administered preoperatively, although the sixth cycle did not include bevacizumab, resulting in 5 weeks between the last bevacizumab dose and surgery. Treatment with bevacizumab plus XELOX was restarted for another six cycles postoperatively. In total, 43 patients were enrolled in the ASSO-LM1 trial. Eight patients were ineligible for resection due to protocol violation and progression in two patients. The resectability of operated patients was 97% with 34 R0 resections and one R1 resection. Postoperative morbidity occurred in 22% of patients, of which three operative revisions were related to the primary tumor resection. Efficacy results for response in 38 eligible patients confirmed an ORR of 66%, 31% SD and 3% PD according to RECIST. Preoperative grade 3/4 adverse events were 17% diarrhea, 5% HFS and 5% thromboembolic events. Overall survival significantly differed depending upon the fulfillment of adjuvant treatment in curative resected patients (59.1 mo vs. 30.8 mo). In conclusion, the ASSO-LM1 trial is a hypothesis-generating study confirming the prognostic benefits of perioperative therapy with XELOX and bevacizumab in patients with metastatic colorectal cancer confined to the liver

Age Related Differences in Monocyte Subsets and Cytokine Pattern during Acute COVID-19&mdash;A Prospective Observational Longitudinal Study

The COVID-19 pandemic drastically highlighted the vulnerability of the elderly population towards viral and other infectious threats, illustrating that aging is accompanied by dysregulated immune responses currently summarized in terms like inflammaging and immunoparalysis. To gain a better understanding on the underlying mechanisms of the age-associated risk of adverse outcome in individuals experiencing a SARS-CoV-2 infection, we analyzed the impact of age on circulating monocyte phenotypes, activation markers and inflammatory cytokines including interleukin 6 (IL-6), IL-8 and tumor necrosis factor (TNF) in the context of COVID-19 disease progression and outcome in 110 patients. Our data indicate no age-associated differences in peripheral monocyte counts or subset composition. However, age and outcome are associated with differences in monocyte activation status. Moreover, a distinct cytokine pattern of IL-6, IL-8 and TNF in elderly survivors versus non-survivors, which consolidates over the time of hospitalization, suggests that older patients with adverse outcomes experience an inappropriate immune response, reminiscent of an inflammaging driven immunoparalysis. Our study underscores the value, necessity and importance of longitudinal monitoring in elderly COVID-19 patients, as dynamic changes after symptom onset can be observed, which allow for a differentiated insight into confounding factors that impact the complex pathogenesis following an infection with SARS-CoV-2