Debate on appropriate triggers for transfusion of allogeneic blood products and their effects on short- and long-term survival in surgical and critically ill patients continue with no definitive ...evidence or decisive resolution. Although transfusion-related immune modulation (TRIM) is well established, its influence on immune competence in the recipient and its effects on cancer recurrence after a curative resection remains controversial. An association between perioperative transfusion of allogeneic blood products and risk for recurrence has been shown in colorectal cancer in randomized trials; whether the same is true for other types of cancer remains to be determined. This article focuses on the laboratory, animal, and clinical evidence to date on the mechanistic understanding of inflammatory and immune-modulatory effects of blood products and their significance for recurrence in the cancer surgical patient.
The rapid detection and evaluation of patients presenting with perioperative neurological dysfunction is of great clinical relevance. Biomarkers have been defined as biological molecules that can be ...used as an indicator of new onset or progression of a biological process or effect of treatment. Biomarkers have become increasingly important in this setting to supplement other modalities of diagnosis such as EEG, sensory- or motor-evoked potential, transcranial Doppler, near-infrared spectroscopy, or imaging methods. A number of neuro-proteins have been identified and are currently under investigation for potential to provide insights into injury severity, outcome, and the ability to monitor cellular damage and molecular events that occur during neurological injury. S100B is a protein released by glial cells and is considered a marker of blood–brain barrier dysfunction. Clinical studies in patients undergoing cardiac and non-cardiac surgery indicate that serum levels of S100B are increased intraoperatively and after operation. The neurone-specific enolase has also been extensively investigated as a potential marker of neuronal injury in the context of cardiac and non-cardiac surgery. A third biomarker of interest is the Tau protein, which has been linked to neurodegenerative disorders. Tau appears to be more specific than the previous two biomarkers since it is only found in the central nervous system. The metalloproteinase and ubiquitin C terminal hydroxylase-L1 (UCH-L1) are the most recently researched markers; however, their usefulness is still unclear. This review presents a comprehensive overview of S100B, neuronal-specific enolase, metalloproteinases, and UCH-L1 in the perioperative period.
Perioperative strategies can significantly influence long-term cancer outcomes. Dexmedetomidine, an α2-adrenoceptor agonist, is increasingly used perioperatively for its sedative, analgesic, ...anxiolytic, and sympatholytic effects. Such actions might attenuate the perioperative promotion of metastases, but other findings suggest opposite effects on primary tumour progression. We tested the effects of dexmedetomidine in clinically relevant models of dexmedetomidine use on cancer metastatic progression.
Dexmedetomidine was given to induce sub-hypnotic to sedative effects for 6–12 h, and its effects on metastasis formation, using various cancer types, were studied in naïve animals and in the context of stress and surgery.
Dexmedetomidine increased tumour-cell retention and growth of metastases of a mammary adenocarcinoma (MADB 106) in F344 rats, Lewis lung carcinoma (3LL) in C57BL/6 mice, and colon adenocarcinoma (CT26) in BALB/c mice. The metastatic burden increased in both sexes and in all organs tested, including lung, liver, and kidney, as well as in brain employing a novel external carotid-artery inoculation approach. These effects were mediated through α2-adrenergic, but not α1-adrenergic, receptors. Low sub-hypnotic doses of dexmedetomidine were moderately beneficial in attenuating the deleterious effects of one stress paradigm, but not of the surgery or other stressors.
The findings call for mechanistic translational studies to understand these deleterious effects of dexmedetomidine, and warrant prospective clinical trials to assess the impact of perioperative dexmedetomidine use on outcomes in cancer patients.
Despite advances in cancer therapy surgery remains one of the most important treatments for solid tumors; however, even with the development of better and less invasive surgical techniques, surgery ...is characterized by the increased risk of tumor metastasis, accelerated growth of pre-existing micrometastasis and cancer recurrence. Total intravenous anesthesia (TIVA) and regional anesthesia have been proposed to improve long-term outcomes after cancer surgery by different mechanisms, including attenuation of the neuroendocrine response, immunosuppression, decreased opioid requirements (opioids promote angiogenesis and tumor growth) and avoidance of volatile inhalational agents. Much of the data that support these ideas originate from laboratory studies, while there is no clear consensus from the retrospective cohort studies to date. Several randomized controlled trials (RCTs) are in progress and may provide a better understanding regarding the role of the anesthesiologist in cancer surgery. The purpose of this review is to summarize the experimental and human data regarding the effect of anesthesia agents and anesthesia techniques on cancer outcomes.
Glutamate is a primary excitatory neurotransmitter in the mammalian CNS. Glutamate released from presynaptic neurons is cleared from the synaptic cleft passively by diffusion and actively by ...glutamate transporters. In this study, the role of glutamate transporters in sensory processing in the spinal cord has been investigated in behavioral, in vivo and in vitro experiments. Intrathecal application of a non-selective glutamate transport inhibitor, l-trans-pyrrolidine-2,4-dicarboxylic acid (10μl of 100μM solution) induced hypersensitivity to peripheral mechanical and thermal stimuli. Topical application of l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM) onto the dorsal surface of the L3–L6 spinal cord increased spontaneous activities, innocuous and noxious stimulus-evoked responses and after-discharges of wide dynamic range neurons in the L4–5 spinal segments. Whole cell recordings made from superficial dorsal horn neurons in an isolated whole spinal cord from newborn rats (2–3 weeks old) revealed that bath-applied l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM) produced partial membrane depolarization, increased spontaneous action potentials with decreased neuronal membrane resistance and time constant, but without significant changes of capacitance. Finally, the amplitude and duration of primary afferent evoked-excitatory postsynaptic currents recorded from neurons in the substantia gelatinosa in the spinal slices from young adult rats (6–8 weeks old) were increased in the presence of l-trans-pyrrolidine-2,4-dicarboxylic acid (100μM). This study indicates that glutamate transporters regulate baseline excitability and responses of dorsal horn neurons to peripheral stimulation, and suggests that dysfunction of glutamate transporters may contribute to certain types of pathological pain.
The relationship between tissue oxygen saturation (StO2) and serious postoperative complications remains unclear. We tested the hypothesis that perioperative StO2 in patients undergoing major ...non-cardiac surgery is inversely related to serious surgical outcomes.
We enrolled 124 patients, ASA physical status ≤IV, having elective major non-cardiac surgeries with general anaesthesia. An InSpectra Model 650 StO2 monitor (Hutchinson Technology, Hutchinson, MN, USA) was used to measure StO2 at the thenar eminence throughout surgery and for two postoperative hours. Our primary outcome was a composite of 30 day mortality and serious in-hospital complications. The secondary outcome was an a priori subset of the primary composite outcome representing infectious and wound-healing complications. Multivariable logistic regression was used to evaluate the associations between our primary and secondary outcomes and time-weighted average (TWA) and minimum StO2.
Patients were 61 (12), mean (sd) yr old. The minimum StO2 was inversely associated with our primary composite outcome (P=0.02). The estimated odds ratio (97.5% CI) of having any major postoperative morbidity was 0.82 (0.67, 1.00) for a 5% increase in the minimum StO2. In contrast, TWA StO2 was not significantly associated with major postoperative morbidity (P=0.35). Furthermore, neither TWA (P=0.65) nor minimum (P=0.70) StO2 was significantly associated with wound complications.
Minimum perioperative peripheral tissue oxygenation predicted a composite of major complications and mortality from major non-cardiac surgery. This is an observational association and whether clinical interventions to augment tissue oxygenation will improve outcomes remains to be determined.
Summary
Published data suggest that the type of general anaesthesia used during surgical resection for cancer may impact on patient long‐term outcome. However, robust prospective clinical evidence is ...essential to guide a change in clinical practice. We explored the feasibility of conducting a randomised controlled trial to investigate the impact of total intravenous anaesthesia with propofol vs. inhalational volatile anaesthesia on postoperative outcomes of patients undergoing major cancer surgery. We undertook a randomised, double‐blind feasibility and pilot study of propofol total intravenous anaesthesia or volatile‐based maintenance anaesthesia during cancer resection surgery at three tertiary hospitals in Australia and the USA. Patients were randomly allocated to receive propofol total intravenous anaesthesia or volatile‐based maintenance anaesthesia. Primary outcomes for this study were successful recruitment to the study and successful delivery of the assigned anaesthetic treatment as per randomisation arm. Of the 217 eligible patients approached, 146 were recruited, a recruitment rate of 67.3% (95%CI 60.6–73.5%). One hundred and forty‐five patients adhered to the randomised treatment arm, 99.3% (95%CI 96.2–100%). Intra‐operative patient characteristics and postoperative complications were comparable between the two intervention groups. This feasibility and pilot study supports the viability of the protocol for a large, randomised controlled trial to investigate the effect of anaesthesia technique on postoperative cancer outcomes. The volatile anaesthesia and peri‐operative outcomes related to cancer (VAPOR‐C) study that is planned to follow this feasibility study is an international, multicentre trial with the aim of providing evidence‐based guidelines for the anaesthetic management of patients undergoing major cancer surgery.
Changes in the signaling of wide dynamic range neurons and the expression of glutamate transporters in the lumbar spinal dorsal horn of rats with Taxol-induced hyperalgesia are detailed in this ...report. Deep spinal lamina neurons have significantly increased spontaneous activity and after-discharges to noxious mechanical stimuli, increased responses to both skin heating and cooling, and increased after-discharges and abnormal windup to transcutaneous electrical stimuli. The expression of glutamate transporter proteins in the dorsal horn is decreased at the time point corresponding to the physiological changes. These results suggest a state of increased excitability develops in spinal pain-signaling neurons as a consequence of decreased glutamate clearance. These changes in dorsal horn neurobiology likely in turn contribute to the hyper-responsiveness to sensory stimuli seen in animals treated with Taxol and may play a role in the pain seen in cancer patients receiving Taxol.
Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was ...that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1(+) neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1(+) neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. Significance statement: In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans.
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