Anesthetics and Long Term Cancer Outcomes: May Epigenetics Be the Key for Pancreatic Cancer?

Knowledge shows a divergence of results between preclinical and clinical studies regarding anesthesia and postoperative progression of cancer. While laboratory and animal data from then 2000s onwards raised much enthusiasm in this field of research leading to several clinical investigations worldwide, data from randomized trials seem to have killed off hope for many scientists. However several aspects of the actual knowledge should be reevaluated and there is space for new strategies of investigation. In this paper, we perform a critical review of actual knowledge and propose new research strategies with a special focus on anesthetic management and repurposed anesthetic adjuvants for pancreatic cancer.

Recurrence Kinetics after Laparoscopic Versus Open Surgery in Colon Cancer. A Meta-Analysis.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of mortality worldwide and in the UK. Surgical resection is the main curative treatment modality available and using a laparoscopic vs. an open approach may have a direct influence on the inflammatory response, influencing cancer biology and potentially the recurrence kinetics by promoting cancer growth. METHODS: This systematic review aims to compare laparoscopic with open surgery for the treatment of colon cancer with a specific focus on the moment of the recurrence. We included randomised controlled trials in intended curative surgery for colon cancer in adults. INTERVENTIONS: Studies investigating laparoscopic vs. open resection as an intended curative treatment for patients with confirmed carcinoma of the colon. The two co-primary outcomes were the time to recurrence and the overall survival (OS) and disease-free survival (DFS) at three and five years. Meta-analyses were done on the mean differences. RESULTS: After selection, we reviewed ten randomised controlled trials. Most of the trials did not display a statistically significant difference in either DFS or OS at three or at five years when comparing laparoscopic to open surgery. Groups did not differ for the OS and DFS, especially regarding the time needed to observe the median recurrence rate. The quality of evidence (GRADE) was moderate to very low. CONCLUSION: We observed no difference in the recurrence kinetics, OS or DFS at three or five years when comparing laparoscopic to open surgery in colon cancer.

Drug Repurposing, an Attractive Strategy in Pancreatic Cancer Treatment: Preclinical and Clinical Updates.

Pancreatic cancer (PC) is one of the deadliest malignancies worldwide, since patients rarely display symptoms until an advanced and unresectable stage of the disease. Current chemotherapy options are unsatisfactory and there is an urgent need for more effective and less toxic drugs to improve the dismal PC therapy. Repurposing of non-oncology drugs in PC treatment represents a very promising therapeutic option and different compounds are currently being considered as candidates for repurposing in the treatment of this tumor. In this review, we provide an update on some of the most promising FDA-approved, non-oncology, repurposed drug candidates that show prominent clinical and preclinical data in pancreatic cancer. We also focus on proposed mechanisms of action and known molecular targets that they modulate in PC. Furthermore, we provide an explorative bioinformatic analysis, which suggests that some of the PC repurposed drug candidates have additional, unexplored, oncology-relevant targets. Finally, we discuss recent developments regarding the immunomodulatory role displayed by some of these drugs, which may expand their potential application in synergy with approved anticancer immunomodulatory agents that are mostly ineffective as single agents in PC.

Metoclopramide and Propofol to Prevent Nausea and Vomiting during Cesarean Section under Spinal Anesthesia: A Randomized, Placebo-Controlled, Double-Blind Trial.

BACKGROUND: Intra-operative nausea, vomiting and retching (NVR) are frequently associated with subarachnoid anesthesia (SA) in women undergoing cesarean section (CS). In this study performed in women undergoing CS under SA with a risk factor control strategy, we compared saline (placebo), propofol, metoclopramide and both drugs to prevent NVR. METHODS: We recorded NVR events in 110 women undergoing CS who were randomized after umbilical cord clamping to receive saline (S; n = 27), metoclopramide 10 mg (M; n = 28), propofol 1 mg/kg/h (P; n = 27) or both drugs (PM; n = 28). RESULTS: The proportion of women with intra-operative nausea was: S: 17/27 (63%); P: 15/27 (56%); M: 13/28 (46%); PM: 6/28 (21%) (p = 0.012, Cramér's V = 0.31 (large effect). The proportion of women with intra-operative vomiting/retching was: S: 9/27 (33%); M: 7/27 (25%); P: 3/28 (11%); PM 2/28 (7%) (p = 0.049, Cramér's V = 0.26 (medium effect). Post-hoc multiple comparisons revealed a significant reduction in NVR episodes and NRS scores between the PM group and control. Sedation scores did not differ among groups. CONCLUSION: In women undergoing CS under SA with a risk factor control strategy, combined propofol and metoclopramide reduce nausea and vomiting.

How Anesthetic, Analgesic and Other Non-Surgical Techniques During Cancer Surgery Might Affect Postoperative Oncologic Outcomes: A Summary of Current State of Evidence.

The question of whether anesthetic, analgesic or other perioperative intervention during cancer resection surgery might influence long-term oncologic outcomes has generated much attention over the past 13 years. A wealth of experimental and observational clinical data have been published, but the results of prospective, randomized clinical trials are awaited. The European Union supports a pan-European network of researchers, clinicians and industry partners engaged in this question (COST Action 15204: Euro-Periscope). In this narrative review, members of the Euro-Periscope network briefly summarize the current state of evidence pertaining to the potential effects of the most commonly deployed anesthetic and analgesic techniques and other non-surgical interventions during cancer resection surgery on tumor recurrence or metastasis.

Pain control with ultrasound-guided inguinal field block compared with spinal anesthesia after hernia surgery: a randomized trial.

BACKGROUND: Inguinal field block (IFB) is a recommended technique for pain control after inguinal hernia repair but is also underused by surgeons. Currently, there is no decisive evidence on which technique, IFB or spinal anesthesia block (SAB), provides better pain control during the first day after hernia repair. In this study, we compared ultrasound-guided IFB performed by anesthesiologists and SAB for pain control during the first day after hernia repair. METHODS: We compared static and dynamic pain scores measured with a numerical rating scale in 86 male patients scheduled for elective unilateral inguinal hernia repair with either ultrasound-guided IFB (n = 42) or SAB (n = 44). RESULTS: Dynamic and static pain at 4 hours (P < .01, r > 0.34, "large effect size"), and dynamic pain the morning after operation (P = .04, r > 0.20, "medium effect size") were less in the field block group compared with the SAB group. Postoperative analgesic consumption was reduced during hospital stay (P = .005, r > 0.34, "large effect size") and for 7 postoperative days in the field block group (P = .03, r > 0.20, "medium effect size"). CONCLUSION: In this study, ultrasound-guided IFB provided lesser dynamic pain scores during the first postoperative day and reduced use of analgesics for 1 week compared with spinal anesthesia after inguinal hernia repair. Our technique could become a substitute performed by anesthesiologists in settings in which IFB is not performed routinely by surgeons.

Analysis of gene copy number variations using a method based on lab-on-a-chip technology.

AIMS AND BACKGROUND: Copy number variations (CNVs) contribute to genome variability and their pathogenic role is becoming evident in an increasing number of human disorders. Commercial assays for routine diagnosis of CNVs are available only for a fraction of known genomic rearrangements. Thus, it is important to develop flexible and cost-effective methods that can be adapted to the detection of CNVs of interest, both in research and clinical settings. METHODS: We describe a new multiplex PCR-based method for CNV analysis that exploits automated microfluidic capillary electrophoresis through lab-on-a-chip technology (LOC-CNV). We tested the reproducibility of the method and compared the results obtained by LOC-CNV with those obtained using previously validated semiquantitative assays such as multiplex ligation-dependent probe amplification (MLPA) and nonfluorescent multiplex PCR coupled to HPLC (NFMP-HPLC). RESULTS: The results obtained by LOC-CNV in control individuals and carriers of pathogenic MLH1 or BRCA1 genomic rearrangements (losses or gains) were concordant with those obtained by previously validated methods, indicating that LOC-CNV is a reliable method for the detection of genomic rearrangements. CONCLUSION: Because of its advantages with respect to time, costs, easy adaptation of previously developed multiplex assays and flexibility in novel assay design, LOC-CNV may represent a practical option to evaluate relative copy number changes in genomic targets of interest, including those identified in genome-wide analyses.

Molecular pathology of oxidative stress in diabetic angiopathy: role of mitochondrial and cellular pathways.

Diabetes mellitus is characterized by chronic hyperglycaemia and a significant risk of developing micro- and macrovascular complications. Growing evidence suggests that increased oxidative stress, induced by several hyperglycaemia-activated pathways, is a key factor in the pathogenesis of endothelial dysfunction and vascular disease. Reactive oxidant molecules, which are produced at a high rate in the diabetic milieu, can cause oxidative damage of many cellular components and activate several pathways linked with inflammation and apoptosis. Among the mechanisms involved in oxidative stress generation, mitochondria and uncoupling proteins are of particular interest and there is growing evidence suggesting their pivotal role in the pathogenesis of diabetic complications. Other important cellular sources of oxidants include nicotinamide adenine dinucleotide phosphate oxidases and uncoupling endothelial nitric oxide synthase. In addition, diabetes is associated with reduced antioxidant defences, which generally contrast the deleterious effect of oxidant species. This concept underlines a potential beneficial role of antioxidant therapy for the prevention and treatment of diabetic vascular disease. However, large scale trials with classical antioxidants have failed to show a significant effect on major cardiovascular events, thus underlying the need of further investigations in order to develop therapies to prevent and/or delay the development of micro- and macrovascular complications.

The molecular basis of diabetic microangiopathy.

Diabetes mellitus is a chronic disease characterized by hyperglycaemia and carbohydrate, fat and protein metabolism abnormalities, all due to an impairment in insulin homeostasis and a diffuse microangiopathy most involving retina, kidney and nerves. Several mechanisms are altered at a molecular level and interplay to develop the slow but devastating clinical impairments related to microangiopathy. Polyol pathway, advanced glycation endproducts, protein kinase C, hexosamine pathway and oxidative stress are among those mechanisms. Molecular pathways of diabetes from hyperglycaemia to signalling cascades alterations and the most promising strategies for successful therapeutic approaches derived from better knowledge of biochemical mechanisms are treated extensively in the present review.