On the horns of a dilemma: choosing total intravenous anaesthesia or volatile anaesthesia for cancer surgery, an enduring controversy.

Two methods for administering general anaesthesia are widely used: propofol-based total intravenous anaesthesia (propofol-TIVA) and inhalation volatile agent-based anaesthesia. Both modalities, which have been standards of care for several decades, boast a robust safety profile. Nevertheless, the potential differential effects of these anaesthetic techniques on immediate, intermediate, and extended postoperative outcomes remain a subject of inquiry. We discuss a recently published longitudinal analysis stemming from a multicentre randomised controlled trial comparing sevoflurane-based inhalation anaesthesia with propofol-TIVA in older patients with cancer, which showed a reduced incidence of emergence and postoperative delirium, comparable postoperative complication rates within 30 days after surgery, and comparable long-term survival rates. We undertake an assessment of the trial's methodological strengths and limitations, contextualise its results within the broader scientific evidence, and explore avenues for resolving the extant controversies in anaesthetic choice for cancer surgery. We aim to pave the way for the incorporation of precision medicine paradigms into the evolving landscape of perioperative care for patients with cancer.

Anesthetic technique and cancer surgery outcomes.

PURPOSE OF REVIEW: Surgery remains integral to treating solid cancers. However, the surgical stress response, characterized by physiologic perturbation of the adrenergic, inflammatory, and immune systems, may promote procancerous pathways. Anesthetic technique per se may attenuate/enhance these pathways and thereby could be implicated in long-term cancer outcomes. RECENT FINDINGS: To date, clinical studies have predominantly been retrospective and underpowered and, thus limit meaningful conclusions. More recently, prospective studies of regional anesthesia for breast and colorectal cancer surgery have failed to demonstrate long-term cancer outcome benefit. However, based on the consistent observation of protumorigenic effects of surgical stress and that of volatile anesthesia in preclinical studies, supported by in vivo models of tumor progression and metastasis, we await robust prospective clinical studies exploring the role of propofol-based total intravenous anesthesia (cf. inhalational volatiles). Additionally, anti-adrenergic/anti-inflammatory adjuncts, such as lidocaine, nonsteroidal anti-inflammatory drugs and the anti-adrenergic propranolol warrant ongoing research. SUMMARY: The biologic perturbation of the perioperative period, compounded by the effects of anesthetic agents, renders patients with cancer particularly vulnerable to enhanced viability of minimal residual disease, with long-term outcome consequences. However, low level and often conflicting clinical evidence equipoise currently exists with regards to optimal oncoanesthesia techniques. Large, prospective, randomized control trials are urgently needed to inform evidence-based clinical practice guidelines.

Layered assemblers for scalable parallel integration.

Many complex natural and artificial systems are composed of large numbers of elementary building blocks, such as organisms made of many biological cells or processors made of many electronic transistors. This modular substrate is essential to the evolution of biological and technological complexity, but has been difficult to replicate for mechanical systems. This study seeks to answer if layered assembly can engender exponential gains in the speed and efficacy of block or cell-based manufacturing processes. A key challenge is how to deterministically assemble large numbers of small building blocks in a scalable manner. Here, we describe two new layered assembly principles that allow assembly faster than linear time, integrating n modules in O(n2/3) and O(n1/3) time: one process uses a novel opto-capillary effect to selectively deposit entire layers of building blocks at a time, and a second process jets building block rows in rapid succession. We demonstrate the fabrication of multi-component structures out of up to 20 000 millimetre scale spherical building blocks in 3 h. While these building blocks and structures are still simple, we suggest that scalable layered assembly approaches, combined with a growing repertoire of standardized passive and active building blocks could help bridge the meso-scale assembly gap, and open the door to the fabrication of increasingly complex, adaptive and recyclable systems.

Modes of carbon dioxide delivery during laparoscopy generate distinct differences in peritoneal damage and hypoxia in a porcine model.

BACKGROUND: Insufflation with CO2 can employ continuous flow, recirculated gas and/or additional warming and humidification. The ability to compare these modes of delivery depends upon the assays employed and opportunities to minimize subject variation. The use of pigs to train colorectal surgeons provided an opportunity to compare three modes of CO2 delivery under controlled circumstances. METHODS: Sixteen pigs were subjected to rectal resection, insufflated with dry-cold CO2 (DC-CO2) (n = 5), recirculated CO2 by an AirSeal device (n = 5) and humidification and warming (HW-CO2) by a HumiGard device (n = 6). Peritoneal biopsies were harvested from the same region of the peritoneum for fixation for immunohistochemistry for hypoxia-inducible factor 1 alpha (HIF-1α) and scanning electron microscopy (SEM) to evaluate hypoxia induction or tissue/cellular damage, respectively. RESULTS: DC-CO2 insufflation by both modes leads to significant damage to mesothelial cells as measured by cellular bulging and retraction as well as microvillus shortening compared with HW-CO2 at 1 to 1.5 h. DC-CO2 also leads to a rapid and significant induction of HIF-1α compared with HW-CO2. CONCLUSIONS: DC-CO2 insufflation induces substantive cellular damage and hypoxia responses within the first hour of application. The use of HW-CO2 insufflation ameliorates these processes for the first one to one and half hours in a large mammal used to replicate surgery in humans.

Preoperative ß-Blockade with Propranolol Reduces Biomarkers of Metastasis in Breast Cancer: A Phase II Randomized Trial.

PURPOSE: The majority of deaths from breast cancer occur following the development of metastatic disease, a process inhibited by ß-blockers in preclinical studies. This phase II randomized controlled trial evaluated the effect of preoperative ß-blockade with propranolol on biomarkers of metastatic potential and the immune cell profile within the primary tumor of patients with breast cancer. PATIENTS AND METHODS: In this triple-blind placebo-controlled clinical trial, 60 patients were randomly assigned to receive an escalating dose of oral propranolol (n = 30; 80-160 mg daily) or placebo (n = 30) for 7 days prior to surgery. The primary endpoint investigated the effect of propranolol on prometastatic and proinflammatory gene expression within the primary tumor. RESULTS: Propranolol downregulated primary tumor expression of mesenchymal genes (P = 0.002) without affecting epithelial gene expression (P = 0.21). Bioinformatic analyses implicated downregulation of Snail/Slug (P = 0.03), NF-κB/Rel (P < 0.01), and AP-1 (P < 0.01) transcription factors in structuring the observed transcriptome alterations, and identified changes in intratumoral neutrophil, natural killer cell, and dendritic cell recruitment (all P < 0.01). Patients with clinical evidence of drug response (lowered heart rate and blood pressure) demonstrated elevated tumor infiltration of CD68+ macrophages and CD8+ T cells. CONCLUSIONS: One week of ß-blockade with propranolol reduced intratumoral mesenchymal polarization and promoted immune cell infiltration in early-stage surgically-resectable breast cancer. These results show that ß-blockade reduces biomarkers associated with metastatic potential, and support the need for larger phase III clinical trials powered to detect the impact of ß-blockade on cancer recurrence and survival.See related commentary by Blaes et al., p. 1781.

Correction to: Anesthetic technique and cancer outcomes: a meta-analysis of total intravenous versus volatile anesthesia.

There was an isolated error relating to the Oh et al. study (1) within our recurrence-free survival analysis. When the reported estimates for Oh et al. are corrected, the pooled hazard ratio (HR) is now 0.87; 95% confidence interval (CI), 0.66 to 1.15; P=0.32.

Anesthetic technique and cancer outcomes: a meta-analysis of total intravenous versus volatile anesthesia.

PURPOSE: Cancer-related mortality, a leading cause of death worldwide, is often the result of metastatic disease recurrence. Anesthetic techniques have varying effects on innate and cellular immunity, activation of adrenergic-inflammatory pathways, and activation of cancer-promoting cellular signaling pathways; these effects may translate into an influence of anesthetic technique on long-term cancer outcomes. To further analyze the effects of propofol (intravenous) and volatile (inhalational gas) anesthesia on cancer recurrence and survival, we undertook a systematic review with meta-analysis. SOURCE: Databases were searched up to 14 November 2018. Comparative studies examining the effect of inhalational volatile anesthesia and propofol-based total intravenous anesthesia (TIVA) on cancer outcomes were included. The Newcastle Ottawa Scale (NOS) was used to assess methodological quality and bias. Reported hazard ratios (HRs) were pooled and 95% confidence intervals (CIs) calculated. PRINCIPAL FINDINGS: Ten studies were included; six studies examined the effect of anesthetic agent type on recurrence-free survival following breast, esophageal, and non-small cell lung cancer (n = 7,866). The use of TIVA was associated with improved recurrence-free survival in all cancer types (pooled HR, 0.78; 95% CI, 0.65 to 0.94; P < 0.01). Eight studies (n = 18,778) explored the effect of anesthetic agent type on overall survival, with TIVA use associated with improved overall survival (pooled HR, 0.76; 95% CI, 0.63 to 0.92; P < 0.01). CONCLUSION: This meta-analysis suggests that propofol-TIVA use may be associated with improved recurrence-free survival and overall survival in patients having cancer surgery. This is especially evident where major cancer surgery was undertaken. Nevertheless, given the inherent limitations of studies included in this meta-analysis these findings necessitate prospective randomized trials to guide clinical practice. TRIAL REGISTRATION: PROSPERO (CRD42018081478); registered 8 October, 2018.

RéSUMé: OBJECTIF: La mortalité liée au cancer, une cause majeure de décès dans le monde entier, est bien souvent le résultat de la récurrence de la maladie métastatique. Les techniques anesthésiques ont des effets variés sur l'immunité naturelle et cellulaire, l'activation des voies adrénergiques inflammatoires, et l'activation des voies de signalisation cellulaire promouvant le cancer; ces effets pourraient se traduire dans une influence de la technique anesthésique sur les pronostics de cancer à long terme. Afin d'approfondir l'analyse des effets de l'anesthésie au propofol (voie intraveineuse) et par inhalation (gaz) sur la récurrence du cancer et la survie, nous avons entrepris une revue systématique avec méta-analyse. SOURCE: Nous avons réalisé des recherches dans les bases de données jusqu'au 14 novembre 2018. Les études comparatives examinant l'effet d'une anesthésie par inhalation et d'une anesthésie intraveineuse totale (TIVA) avec propofol sur les pronostics de cancer ont été incluses dans notre revue. L'échelle de Newcastle-Ottawa (NOS) a été utilisée pour évaluer la qualité méthodologique et le biais. Les rapports de risque (RR) rapportés ont été pondérés et les intervalles de confiance (IC) à 95 % calculés. CONSTATATIONS PRINCIPALES: Dix études ont été incluses; six études ont examiné l'effet du type d'agent anesthésique sur la survie sans récurrence après un cancer du sein, de l'œsophage et du cancer pulmonaire non à petites cellules (n = 7866). L'utilisation d'une TIVA était associée à une amélioration de la survie sans récurrence, tous types de cancer confondus (RR pondéré, 0,78; IC 95 %, 0,65 à 0,94; P < 0,01). Huit études (n = 18 778) ont exploré l'effet du type d'agent anesthésique sur la survie globale, l'utilisation d'une TIVA étant alors associée à une amélioration de la survie globale (RR pondéré, 0,76; IC 95 %, 0,63 à 0,92; P < 0,01). CONCLUSION: Cette méta-analyse suggère que l'administration d'une TIVA à base de propofol pourrait être associée à une amélioration de la survie sans récurrence et de la survie globale chez les patients subissant une chirurgie oncologique. Cette observation est particulièrement frappante dans les cas de chirurgie oncologique majeure. Toutefois, étant donné les lacunes inhérentes des études incluses dans cette méta-analyse, ces résultats nécessitent la réalisation d'études randomisées prospectives afin d'éclairer la pratique clinique. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42018081478); enregistrée le 8 octobre 2018.

Perioperative events influence cancer recurrence risk after surgery.

Surgery is a mainstay treatment for patients with solid tumours. However, despite surgical resection with a curative intent and numerous advances in the effectiveness of (neo)adjuvant therapies, metastatic disease remains common and carries a high risk of mortality. The biological perturbations that accompany the surgical stress response and the pharmacological effects of anaesthetic drugs, paradoxically, might also promote disease recurrence or the progression of metastatic disease. When cancer cells persist after surgery, either locally or at undiagnosed distant sites, neuroendocrine, immune, and metabolic pathways activated in response to surgery and/or anaesthesia might promote their survival and proliferation. A consequence of this effect is that minimal residual disease might then escape equilibrium and progress to metastatic disease. Herein, we discuss the most promising proposals for the refinement of perioperative care that might address these challenges. We outline the rationale and early evidence for the adaptation of anaesthetic techniques and the strategic use of anti-adrenergic, anti-inflammatory, and/or antithrombotic therapies. Many of these strategies are currently under evaluation in large-cohort trials and hold promise as affordable, readily available interventions that will improve the postoperative recurrence-free survival of patients with cancer.

Impact of celecoxib on inflammation during cancer surgery: a randomized clinical trial.

PURPOSE: During cancer surgery, prostaglandin-mediated inflammation may promote and activate micrometastatic disease with a consequent increase in long-term cancer recurrence. Cyclooxygenase-2 inhibitors, known to have anti-proliferative properties, may offset such perioperative perturbation. We investigated the effectiveness of these agents to minimize inflammatory changes during cancer surgery. METHODS: Following ethics approval, 32 patients who were to undergo major intracavity cancer surgery were enrolled in this prospective, randomized, clinical trial. The treatment group received 400 mg celecoxib preoperatively followed by five 200 mg 12-hourly doses. The control group received no anti-inflammatory agents. Inflammatory and immunomodulatory end points were measured serially. The primary end points were the measured plasma and urinary prostaglandin E metabolite (PGEM) levels 48 hours following surgery. Secondary endpoints included interleukin levels, leucocyte profile, and clinical end points. RESULTS: No differences in the 48-hr plasma or urinary PGEM levels were observed between the celecoxib and control groups. Linear mixed modeling, used to accommodate differences in baseline PGEM levels, showed that celecoxib (cf. control) administration lowered plasma PGEM over the entire 48-hr period following surgery (ß-coefficient = -0.38 pg.ml-1; 95% confidence interval: -0.69 to -0.06; P = 0.021). Celecoxib administration also lowered postoperative pain scores. DISCUSSION: Standard dosing of the cyclooxygenase-2 inhibitor celecoxib slightly reduced perioperative cyclooxygenase activity during cancer surgery. Given cyclooxygenase's role in cancer pathways, we recommend dose-finding studies be undertaken before prospective clinical trials are conducted testing the currently unsubstantiated hypothesis that perioperative anti-inflammatory administration improves long-term cancer outcomes. This trial was registered at: Australian New Zealand Clinical Trial Registry: ACTRN12615000041550; www.anzctr.org.au.

Neuraxial Anesthesia Reduces Lymphatic Flow: Proof-of-Concept in First In-Human Study.

Dilation of lymphatic vessels may contribute to iatrogenic dissemination of cancer cells during surgery. We sought to determine whether neuraxial anesthesia reduces regional lymphatic flow. Using nuclear lymphoscintigraphy, 5 participants receiving spinal anesthesia for brachytherapy had lower extremity lymph flow at rest compared with flow under conditions of spinal anesthesia. Six limbs were analyzed. Four limbs were excluded because of failure to demonstrate lymph flow (1 patient, 2 limbs), colloid injection error (1 limb), and undiagnosed deep vein thrombosis (1 limb). All analyzed limbs showed reduced lymph flow washout from the pedal injection site (range 62%-100%) due to neuraxial anesthesia. Lymph flow was abolished in 3 limbs. We report proof-of-concept that neuraxial anesthesia reduces lymphatic flow through a likely mechanism of sympathectomy.

Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

Understanding clinical strategies that may impact tumour growth and metastatic spread at the time of cancer surgery.

The role of the perioperative period during cancer surgery and its impact on patients' long-term cancer outcomes are of increasing interest. Anticipation and prevention of perioperative immunosuppression and targeted therapeutic interventions that translate to reduced cancer recurrence are increasingly being explored. These interventions may focus on reducing the systemic inflammatory response, the regional lymphatic flow induced by surgical inflammation and exposure to perioperative immunosuppressive agents. The challenge has been to provide evidence-based links between these hypothesised cancer 'reducing' strategies, our knowledge of cancer biology and tangible long-term clinical outcomes of improved recurrence-free and overall survival. Anaesthesiologists caring for patients with cancer may preferentially employ regional anaesthesia techniques and anti-inflammatory agents to minimise perioperative immunosuppression and preserve perioperative homeostasis. However, prospective trials powered for long-term cancer outcomes are necessary to provide an evidence base before these strategies are to be recommended for routine clinical practice.