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.

Perioperative events influence cancer recurrence risk after surgery.

Background: Surgical resection remains the best option for long-term survival in many solid tumors. Surgery can, however, lead to tumor cell release into the circulation. Data have suggested differential effects of anesthetic agents on cancer cell growth. This retrospective analysis investigated the association of anesthetic technique with long-term survival in patients presenting for elective surgery in a comprehensive cancer center over 3 yr. Methods: All patients undergoing elective surgery between June 2010 and May 2013 were included. Patients were grouped according to whether they had received volatile inhalational (INHA) or total IV anesthesia (TIVA). After excluding those who received both forms of anesthesia during the study period, Kaplan-Meier survival curves were constructed from the date of surgery to death. After propensity matching, univariate and multivariable regression models were used to compare hazard ratios for death. Results: A total of 11,395 anesthetics using INHA or TIVA were delivered in the study period. After exclusions, 3,316 patients (796 deaths, 24%) remained in the INHA group and 3,714 (504 deaths, 13.5%) in the TIVA group. After propensity matching, 2,607 patients remained in each group (597 deaths, 22.8%, in INHA group vs. 407, 15.6%, in TIVA group). Volatile inhalational anesthesia was associated with a hazard ratio of 1.59 (1.30 to 1.95) for death on univariate analysis and 1.46 (1.29 to 1.66) after multivariable analysis of known confounders in the matched group. Conclusions: This retrospective analysis demonstrates an association between type of anesthetic delivered and survival. This analysis alongside biological plausibility should lead to urgent prospective work exploring the effect of anesthetic technique on survival. (Anesthesiology 2016; 124: 69-79)

Long-term Survival for Patients Undergoing Volatile versus IV Anesthesia for Cancer Surgery: A Retrospective Analysis.

Prostate cancer cell malignancy via modulation of HIF-1 α pathway with isoflurane and propofol alone and in combination

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Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination.

Volatile general anesthetics continue to be an important part of clinical anesthesia worldwide The impact of volatile anesthetics on the immune system has been investigated at both mechanistic and clinical levels, but previous studies have returned conflicting findings due to varied protocols, experimental environments, and subject species While many of these studies have focused on the immunosuppressive effects of volatile anesthetics, compelling evidence also exists for immunoactivation Depending on the clinical conditions, immunosuppression and activation due to volatile anesthetics can be either detrimental or beneficial This review provides a balanced perspective on the anesthetic modulation of innate and adaptive immune responses as well as indirect effectors of immunity Potential mechanisms of immunomodulation by volatile anesthetics are also discussed A clearer understanding of these issues will pave the way for clinical guidelines that better account for the impact of volatile anesthetics on the immune system, with the ultimate goal of improving perioperative management

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Immune Modulation by Volatile Anesthetics

Background Animal models and retrospective clinical data suggest that certain anaesthetic techniques can attenuate immunosuppression and minimize metastasis after cancer surgery. Natural killer (NK) T cells are a critical component of the anti-tumour immune response. We investigated the effect of serum from women undergoing primary breast cancer surgery, randomized to propofol–paravertebral block (PPA) or sevoflurane–opioid (GA) anaesthetic techniques, on healthy human donor NK cell function and cytotoxicity against oestrogen and progesterone receptor-positive breast cancer cells (HCC1500). Methods Ten subjects who donated serum before operation and 24 h after operation in an ongoing randomized prospective trial (NCT 00418457) were randomly selected. Serum from PPA ( n =5) and GA ( n =5) subjects was co-cultured with HCC1500 and healthy primary NK cells. NK cell activating receptors (NKp30, NKp44, NKp46, 2b4, CD16, NKG2D), cytokine production, NK CD107a expression, and cytotoxicity towards HCC1500 were examined. Results Serum from PPA subjects did not alter normal NK marker expression or secretion of cytokines. Serum from GA subjects reduced NK cell activating receptor CD16 [from mean (sem), 82 (2)% to 50 (4)%, P =0.001], IL-10 [from 1700 (80) to 1200 (92) pg ml −1 , P =0.001], and IL-1β [from 68 (12) to 19 (4) pg ml −1 , P =0.01]. An increase in NK cell CD107a [23 (2)% to 37(3)%, P =0.007] and apoptosis of HCC1500 [11 (1)% to 21 (2)%, P =0.0001] was observed with PPA serum, but not GA serum, treated NK cells. Conclusion Serum from women with breast cancer undergoing surgical excision who were randomized to receive a PPA anaesthetic technique led to greater human donor NK cell cytotoxicity in vitro compared with serum from women who received GA. Clinical trial registration NCT 041857.

Effect of anaesthetic technique on the natural killer cell anti-tumour activity of serum from women undergoing breast cancer surgery: a pilot study.

Background:Growing evidence indicates that perioperative factors, including choice of anesthetic, affect cancer recurrence after surgery although little is known about the effect of anesthetics on cancer cells themselves. Certain anesthetics are known to affect hypoxia cell signaling mechanisms in healthy cells by up-regulating hypoxia-inducible factors (HIFs). HIFs are also heavily implicated in tumorigenesis and high levels correlate with poor prognosis.Methods:Renal cell carcinoma (RCC4) cells were exposed to isoflurane for 2 h at various concentrations (0.5–2%). HIF-1α, HIF-2α, phospho-Akt, and vascular endothelial growth factor A levels were measured by immunoblotting at various time points (0–24 h). Cell migration was measured across various components of extracellular matrix, and immunocytochemistry was used to analyze proliferation rate and cytoskeletal changes.Results:Isoflurane up-regulated levels of HIF-1α and HIF-2α and intensified expression of vascular endothelial growth factor A. Exposed cultures contained significantly more cells (1.81 ± 0.25 vs. 1.00 of control; P = 0.03) and actively proliferating cells (89.4 ± 2.80 vs. 64.74 ± 7.09% of control; P = 0.016) than controls. These effects were abrogated when cells were pretreated with the Akt inhibitor, LY294002. Exposed cells also exhibited greater migration on tissue culture–coated (F = 16.89; P = 0.0008), collagen-coated (F = 20.99; P = 0.0003), and fibronectin-coated wells (F = 8.21; P = 0.011) as along with dramatic cytoskeletal rearrangement, with changes to both filamentous actin and α-tubulin.Conclusions:These results provide evidence that a frequently used anesthetic can exert a protumorigenic effect on a human cancer cell line. This may represent an important contributory factor to high recurrence rates observed after surgery.

Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro.

A megabase genome assembly for Aporrectodea caliginosa is presented with transcriptomic and SNP-based evidence for acclimatisation and adaption to extreme weather conditions found at high altitude. Here, we explore the high-altitude adaptions and acclimatisation of Aporrectodea caliginosa. Population diversity is assessed through mitochondrial barcoding, identifying closely related populations across the island of Pico (Azores). We present the first megabase N50 assembly size (1.2 Mbp) genome for A. caliginosa. High- and low-altitude populations were exposed experimentally to a range of oxygen and temperature conditions, simulating altitudinal conditions, and the transcriptomic responses explored. SNP densities are assessed to identify signatures of selective pressure and their link to differentially expressed genes. The high-altitude A. caliginosa population had lower differential expression and fewer co-expressed genes between conditions, indicating a more condition-refined epigenetic response. Genes identified as under adaptive pressure through Fst and nucleotide diversity in the high-altitude population clustered around the differentially expressed an upstream environmental response control gene, HMGB1. The high-altitude population of A. caliginosa indicated adaption and acclimatisation to high-altitude conditions and suggested resilience to extreme weather events. This mechanistic understanding could help offer a strategy in further identifying other species capable of maintaining soil fertility in extreme environments.

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Molecular insights into high-altitude adaption and acclimatisation of Aporrectodea caliginosa

By identifying fragments of DNA in the environment, eDNA approaches present a promising tool for monitoring biodiversity in a cost-effective way. This is particularly pertinent for countries where traditional morphological monitoring has been sparse. The first step to realising the potential of eDNA is to develop methodologies that are adapted to local conditions. Here, we test field and laboratory eDNA protocols (aqueous and sediment samples) in a range of semi-arid ecosystems in Namibia. We successfully gathered eDNA data on a broad suite of organisms at multiple trophic levels (including algae, invertebrates and bacteria) but identified two key challenges to the implementation of eDNA methods in the region: 1) high turbidity requires a tailored sampling technique and 2) identification of taxa by eDNA methods is currently constrained by a lack of reference data. We hope this work will guide the deployment of eDNA biomonitoring in the arid ecosystems of Namibia and neighbouring countries.

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Iain A. Perry

Papers

Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro.

Molecular insights into high-altitude adaption and acclimatisation of Aporrectodea caliginosa

Challenges to Implementing Environmental-DNA Monitoring in Namibia