Anesthesia is a routine component of cancer care that is used for diagnostic and therapeutic procedures. The anesthetic technique has recently been implicated in impacting long-term cancer outcomes, possibly through modulation of adrenergic-inflammatory responses that impact cancer cell behavior and immune cell function. Emerging evidence suggests that propofol-based total intravenous anesthesia (TIVA) may be beneficial for long-term cancer outcomes when compared to inhaled volatile anesthesia. However, the available clinical findings are inconsistent. Preclinical studies that identify the underlying mechanisms involved are critically needed to guide the design of clinical studies that will expedite insight. Most preclinical models of anesthesia have been extrapolated from the use of anesthesia in in vivo research and are not optimally designed to study the impact of anesthesia itself as the primary endpoint. This paper describes a method for delivering propofol-TIVA anesthesia in a mouse model of breast cancer resection that replicates key aspects of clinical delivery in cancer patients. The model can be used to study mechanisms of action of anesthesia on cancer outcomes in diverse cancer types and can be extrapolated to other non-cancer areas of preclinical anesthesia research.
(1) Background: Patients with severe chronic kidney disease (CKD G4-G5) often have chronically elevated high-sensitivity cardiac troponin T (hs-cTnT) values above the 99th percentile of the upper reference limit. In these patients, optimal cutoff levels for diagnosing non-ST-elevation acute coronary syndrome (NSTE-ACS) requiring revascularization remain undefined. (2) Methods: Of 11,912 patients undergoing coronary angiography from 2012 to 2017 for suspected NSTE-ACS, 325 (3%) had severe CKD. Of these, 290 with available serial hs-cTnT measurements were included, and 300 matched patients with normal renal function were selected as a control cohort. (3) Results: In the CKD cohort, 222 patients (76%) had NSTE-ACS with indication for coronary revascularization. Diagnostic performance was high at presentation and similar to that of the control population (AUC, 95% CI: 0.81, 0.75-0.87 versus 0.85, 0.80-0.89, p = 0.68), and the ROC-derived cutoff value was 4 times higher compared to the conventional 99th percentile. Combining the ROC-derived cutoff levels for hs-cTnT at presentation and absolute 3 h changes, sensitivity increased to 98%, and PPV and NPV improved up to 93% and 86%, respectively. (4) Conclusions: In patients with severe CKD and suspected ACS, the diagnostic accuracy of hs-cTnT for the diagnosis of NSTE-ACS requiring revascularization is improved by using higher assay-specific cutoff levels combined with early absolute changes.
Summary Background and Aims Phase III trials have established atezolizumab plus bevacizumab as the novel standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, these trials raised concerns regarding treatment efficacy in non‐viral HCC, and it remains unclear whether combination immunotherapy is safe and effective in patients with advanced cirrhosis. Methods One hundred patients with unresectable HCC initiated therapy with atezolizumab plus bevacizumab at our centre between January 2020 and March 2022. The control cohort consisted of 80 patients with advanced HCC who received either sorafenib ( n = 43) or lenvatinib ( n = 37) as systemic treatment. Results Overall survival (OS) and progression‐free survival (PFS) were significantly longer within the atezolizumab/bevacizumab group and comparable to phase III data. The benefits in terms of increased objective response rate (ORR), OS and PFS were consistent across subgroups, including non‐viral HCC (58%). The ROC‐optimised neutrophil‐to‐lymphocyte ratio (NLR) cut‐off of 3.20 was the strongest independent predictor of ORR and PFS. In patients with advanced cirrhosis Child–Pugh B, liver function was significantly better preserved with immunotherapy. Patients with Child–Pugh B cirrhosis showed similar ORR but shorter OS and PFS compared to patients with preserved liver function. Conclusions Atezolizumab plus bevacizumab showed good efficacy and safety in patients with unresectable HCC and partially advanced liver cirrhosis in a real‐world setting. Moreover, the NLR was able to predict response to atezolizumab/bevacizumab treatment and may guide patient selection.
Surgery is essential for curative treatment of solid tumors. Evidence from recent retrospective clinical analyses suggests that use of propofol-based total intravenous anesthesia during cancer resection surgery is associated with improved overall survival compared to inhaled volatile anesthesia. Evaluating these findings in prospective clinical studies is required to inform definitive clinical guidelines but will take many years and requires biomarkers to monitor treatment effect. Therefore, we examined the effect of different anesthetic agents on cancer recurrence in mouse models of breast cancer with the overarching goal of evaluating plausible mechanisms that could be used as biomarkers of treatment response.To test the hypothesis that volatile anesthesia accelerates breast cancer recurrence after surgical resection of the primary tumor, we used three mouse models of breast cancer. We compared volatile sevoflurane anesthesia with intravenous propofol anesthesia and used serial non-invasive bioluminescent imaging to track primary tumor recurrence and metastatic recurrence. To determine short-term perioperative effects, we evaluated the effect of anesthesia on vascular integrity and immune cell changes after surgery in animal models.Survival analyses found that the kinetics of cancer recurrence and impact on survival were similar regardless of the anesthetic agent used during cancer surgery. Vascular permeability, immune cell infiltration and cytokine profiles showed no statistical difference after resection with inhaled sevoflurane or intravenous propofol anesthesia.These preclinical studies found no evidence that choice of anesthetic agent used during cancer resection surgery affected either short-term perioperative events or long-term cancer outcomes in mouse models of breast cancer. These findings raise the possibility that mouse models do not recapitulate perioperative events in cancer patients. Nonetheless, the findings suggest that future evaluation of effects of anesthesia on cancer outcomes should focus on cancer types other than breast cancer.
Background: Patients with severe chronic kidney disease (CKD G4-G5) often have chronically elevated high-sensitivity cardiac troponin T (hs-cTnT) values above the 99th percentile of the upper reference limit. In these patients, optimal cutoff levels for diagnosing non-ST-elevation acute cor-onary syndrome (NSTE-ACS) requiring revascularization remain undefined.
Methods: Of 11,912 patients undergoing coronary angiography from 2012 to 2017 for suspected NSTE-ACS, 325 (3%) had severe CKD. Of these, 290 with available serial hs-cTnT measurements were included and 300 matched patients with normal renal function were selected as a control cohort. Results: Diagnostic performance for patients with severe CKD was high at presentation and similar to that of the control population (AUC, 95% CI: 0.81, 0.75-0.87 versus 0.85, 0.80-0.89, p=0.68) and the ROC-derived cutoff value at presentation was 4 times higher compared to the conventional 99th percentile. Combining the ROC-derived cutoff levels for hs-cTnT at presentation and absolute 3-hour changes, sensitivity increased to 98%, PPV and NPV improved up to 93% and 86%, re-spectively. (4) Conclusions: In patients with severe CKD and suspected ACS the diagnostic accu-racy of hs-cTnT for the diagnosis of NSTE-ACS requiring revascularization is improved by using higher assay specific cutoff levels combined with early absolute changes.
On the basis of the results of the IMBRAVE-150 trial, the combination of atezolizumab, a programmed cell death ligand 1 (PD-L1) antibody, as well as bevacizumab, a vascular endothelial growth factor (VEGF) antibody, represents a promising novel first-line therapy in patients with advanced hepatocellular carcinoma (HCC). Despite favorable safety data, serious adverse events have been described. However, central nervous system complications such as encephalitis have rarely been reported. We present the case of a 70-year-old woman with hepatitis C virus (HCV)-related liver cirrhosis and advanced HCC who developed severe encephalitis after only one cycle of atezolizumab/bevacizumab.Ten days after administration, the patient presented with confusion, somnolence, and emesis. Within a few days, the patient's condition deteriorated, and mechanical ventilation became necessary.Cerebrospinal fluid (CSF) analysis showed increased cell count and elevated protein values. Further work-up revealed no signs of an infectious, paraneoplastic, or other autoimmune cause.Suspecting an atezolizumab/bevacizumab-related encephalitis, we initiated a high-dose steroid pulse therapy as well as repeated plasmapheresis, which resulted in clinical improvement and remission of CSF abnormalities.Despite successful weaning and transfer to a rehabilitation ward, the patient died of progressive liver cancer 76 days after initial treatment with atezolizumab/bevacizumab, showing no response.This case illustrates that rapid immunosuppressive treatment with prednisolone can result in remission even of severe encephalitis. We discuss this case in the context of available literature and previously reported cases of atezolizumab-induced encephalitis in different tumor entities, highlighting the diagnostic challenges in oncologic patients treated with immune checkpoint-inhibitors.
Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed. Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide. Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression. Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone. Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.
The implementation of immune checkpoint inhibitors (ICI) into the clinical management of different malignancies has largely changed our understanding of cancer treatment. After having proven efficacy in different tumor entities such as malignant melanoma and lung cancer, ICI were intensively tested in the setting of hepatocellular carcinoma (HCC). Here they could achieve higher and more durable response rates compared to tyrosine-kinase inhibitors (TKI), that were sole standard of care for the last decade. Most recently, ICI treatment was approved in a first line setting of HCC, for cases not suitable for curative strategies. However, only a subset of patients benefits from ICI therapy, while others experience rapid tumor progression, worsening of liver function and poor prognosis. Efforts are being made to find immune characteristics that predict tumor responsiveness to ICI, but no reliable biomarker could be identified so far. Nevertheless, data convincingly demonstrate that combination therapies (such as dual inhibition of PD-L1 and VEGF) are more effective than the application of single agents. In this review, we will briefly recapitulate the current algorithms for systemic treatment, discuss available results from checkpoint inhibitor trials and give an outlook on future directions of immunotherapy in HCC.