Effect of anterior quadratus lumborum block with ropivacaine on the immune response after laparoscopic surgery in colon cancer: a substudy of a randomized clinical trial.

BACKGROUND: Surgery induces a temporal change in the immune system, which might be modified by regional anesthesia. Applying a bilateral preoperative anterior quadratus lumborum block has proven to be a safe and effective technique in pain management after abdominal and retroperitoneal surgery, but the effect on the immune response is not thoroughly investigated. METHODS: This study is a substudy of a randomized, controlled, double-blinded trial of patients undergoing laparoscopic hemicolectomy due to colon cancer. Twenty-two patients were randomized to undergo either a bilateral anterior quadratus lumborum nerve block with a total of 60 mL ropivacaine 0.375% or placebo with corresponding isotonic saline injections. The main objective of this exploratory substudy was to investigate the systemic immune response in the first postoperative day by examining changes in blood transcript levels (n=750) and stimulated secretion of cytokines (n=17) on ex vivo activation with microbial ligands and anti-CD3/CD28. RESULTS: Using unsupervised data analysis tools, we observed no effect of the bilateral anterior quadratus lumborum nerve block on gene expression in immune cells (permutational multivariate analysis of variance using distance matrices: F=0.52, p=0.96), abundances of major immune cell populations (Wilcoxon rank-sum test: p>0.05), and stimulated cytokine secretion (Wilcoxon rank-sum test: p>0.05). CONCLUSIONS: Our study provides evidence that administration of bilateral anterior quadratus lumborum nerve block as a part of a multimodal analgesic regimen in an enhanced recovery after surgery for laparoscopic hemicolectomy in this cohort does not alter the systemic immune response.Trial registration number NCT03570541.

Calcium electroporation of esophageal cancer induces gene expression changes: a sub-study of a phase I clinical trial.

PURPOSE: In this study, we aim to investigate gene expression changes in tumor samples obtained from patients with esophageal cancer treated with calcium electroporation. Previously, local treatment with calcium electroporation has been shown to induce gene expression alterations, potentially contributing to a more tumor-hostile microenvironment. METHODS: In this sub-study of a phase I clinical trial, we included five patients with esophageal cancer treated with calcium electroporation. We compared cancer-associated gene expression patterns in tumor samples before and after treatment. Furthermore, we used linear support vector regression to predict the cellular composition of tumor samples. RESULTS: Using differential expression analysis, we identified the downregulation of CXCL14 and upregulation of CCL21, ANGPTL4, and CRABP2 genes. We also found a decreased predicted proportion of dendritic cells while the proportion of neutrophils was increased. CONCLUSION: This study provides evidence that calcium electroporation for esophageal cancer induces local transcriptional changes and possibly alters the cellular composition of the tumor microenvironment. The results are explorative, larger studies are needed to confirm and further correlate our findings with clinical outcomes.

Neoadjuvant intratumoral influenza vaccine treatment in patients with proficient mismatch repair colorectal cancer leads to increased tumor infiltration of CD8+ T cells and upregulation of PD-L1: a phase 1/2 clinical trial.

BACKGROUND: In colorectal cancer, the effects of immune checkpoint inhibitors are mostly limited to patients with deficient mismatch repair tumors, characterized by a high grade infiltration of CD8+T cells. Interventions aimed at increasing intratumoral CD8+T-cell infiltration in proficient mismatch repair tumors are lacking. METHODS: We conducted a proof of concept phase 1/2 clinical trial, where patients with non-metastasizing sigmoid or rectal cancer, scheduled for curative intended surgery, were treated with an endoscopic intratumorally administered neoadjuvant influenza vaccine. Blood and tumor samples were collected before the injection and at the time of surgery. The primary outcome was safety of the intervention. Evaluation of pathological tumor regression grade, immunohistochemistry, flow cytometry of blood, tissue bulk transcriptional analyses, and spatial protein profiling of tumor regions were all secondary outcomes. RESULTS: A total of 10 patients were included in the trial. Median patient age was 70 years (range 54-78), with 30% women. All patients had proficient mismatch repair Union of International Cancer Control stage I-III tumors. No endoscopic safety events occurred, with all patients undergoing curative surgery as scheduled (median 9 days after intervention). Increased CD8+T-cell tumor infiltration was evident after vaccination (median 73 vs 315 cells/mm2, p<0.05), along with significant downregulation of messenger RNA gene expression related to neutrophils and upregulation of transcripts encoding cytotoxic functions. Spatial protein analysis showed significant local upregulation of programmed death-ligand 1 (PD-L1) (adjusted p value<0.05) and downregulation of FOXP3 (adjusted p value<0.05). CONCLUSIONS: Neoadjuvant intratumoral influenza vaccine treatment in this cohort was demonstrated to be safe and feasible, and to induce CD8+T-cell infiltration and upregulation of PD-L1 proficient mismatch repair sigmoid and rectal tumors. Definitive conclusions regarding safety and efficacy can only be made in larger cohorts. TRIAL REGISTRATION NUMBER: NCT04591379.

Effect of 24 mg dexamethasone preoperatively on surgical stress, pain and recovery in robotic-assisted laparoscopic hysterectomy.

Background: Robotic-assisted hysterectomy is an alternative to laparoscopic surgery as part of a minimal invasive regimen. Several treatment strategies are followed to improve the overall outcome and minimize surgical stress. Glucocorticoids provide significant analgesic and antiemetic effects but their role in reducing inflammatory stress in a fast-track, multi-modal setting in patients undergoing minimally invasive surgery remains to be investigated in details. Methods: This study will evaluate in a randomized trial the effect of a single dose of 24 mg dexamethasone on 100 women undergoing robotic-assisted hysterectomy with regard to surgical stress, measured by c-reactive protein as primary outcome and, further, other stress markers like white blood cell subtypes. The postoperative recovery will be registered in validated charts and questionnaires for pain and analgesic use, quality of recovery, incontinence, sexual and work life. Furthermore, in a sub-analysis, transcriptional profiling will be performed to explore the mechanism of systemic innate and adaptive immune system perturbation induced by surgical stress. Conclusion: The study will provide solid evidence on markers of immunomodulation biomarkers and in addition the subjective effects and underlying mechanisms of perioperative glucocorticoid in women undergoing robotic hysterectomy. These include important aspects of life quality like pain, fatigue, freedom of medications, resuming work and sexual activities.