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Efficacy of 48-hour intravenous (IV) lidocaine infusions in open colorectal surgery.

ABSTRACT: Interventions: Patients undergoing elective open colorectal surgery were randomised into the lidocaine group or control group. The lidocaine group received 1.5 mg/kg i.v. bolus at induction of anaesthesia immediately followed by 1 mg/kg/hr i.v. infusion for a total of 48 hours duration. On arrival at the post-anaesthesia care unit (PACU), all patients were connected to an i.v. fentanyl patient-controlled analgesia (PCA) pump (20 mcg bolus, 5 min lockout, maximum dose 240 mcg/hr). PCA fentanyl consumption and numerical pain rating scale (NRS, 0-10) at rest were recorded by a blinded non-study nurse at 30min, 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours post-surgery. A blinded non-study pain physician monitored the patient daily, and adjusted the PCA dose if pain was not controlled. Primary outcome(s): Time to first bowel movement. The nurse caring for the patient filled out a study-specific questionnaire form documenting time of return of first bowel movement and flatus, and adverse effects.[Time (hours) from arrival in the post-anaesthesia care unit (PACU).] Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Efficacy

DISEASE(S): Anaesthesiology-pain Management,Bowel Cancer,Surgery-other Surgery,Colorectal Surgery,Ileus,Inflammatory Bowel Disease

PROVIDER: 2463525 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Estrogen receptor alpha (ERa) is overexpressed in 70% of diagnosed BCa patients and androgen receptor (AR) is overexpressed in 80-90% of diagnosed PCa patients. Thus, BCa and PCa patients are given therapy that reduces hormone levels or directly blocks HR activity; but most patients eventually develop treatment resistance. 15-30% of BCa patients and ≥ 30% of PCa patients that acquire treatment resistance develop tumors enriched in cancer cells with low or no HR accumulation. Furthermore, 15-20% of BCa patients and 10-20% of PCa patients are intrinsically HR-negative (HR-), and thus, have intrinsic resistance to therapy. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERa and AR mRNA in HR-positive (HR+) BCa and PCa cell lines. Additionally, we had identified pro-survival proteins and processes upregulated by IL-1 in HR+ BCa and PCa cells, that are basally high in HR- BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR+ BCa and PCa cells that mimics conserved basal gene expression patterns in HR- BCa and PCa cells, to promote HR-independent survival and tumorigenicity. Methods: To identify changes in global gene expression we performed RNA sequencing (RNA-seq) for HR+ BCa and PCa cell lines exposed to IL-1 and for untreated HR- BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in BCa and PCa cell lines. We also compared our gene expression data with publicly available data sets from hormone receptor-independent sublines. Finally, we performed Ingenuity Pathway Analysis (IPA) to identify signaling pathways encode by our RNA-seq data set. Results: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR+ cells that are, respectively, basally high or low in HR- cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR- BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in hormone receptor-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired treatment resistance. We also assessed HR- cell line viability in response verteporfin, an FDA approved therapy for macular degeneration known to target p62, and we found that verteporfin is cytotoxic for HR- cells lines. Conclusions: Taken together, our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic hormone receptor-independent BCa and PCa.

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Efficacy of 48-hour intravenous (IV) lidocaine infusions in open colorectal surgery.

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