Jonathan G. Hiller

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.

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.

The Combined Blockade of β-Adrenoceptor and COX-2 During the Perioperative Period to Improve Long-term Cancer Outcomes.

For most patients with cancer, the surgical removal of the primary tumor is a necessary and lifesaving intervention. Yet, accumulating evidence suggests that different aspects of surgery and the accompanying stress response also facilitate cancer progression through various mechanisms. For example, general anesthesia (GA), analgesic and sedative agents, blood transfusions, and hypothermia are all associated with increased recurrence and metastatic disease. Specifically, the excision of the tumor induces a cascade of events that facilitate cancer progression. Although surgeons commonly achieve negative margins, the unavoidable tissue damage and mechanical manipulation of the tumor and its blood vessels causes shedding of tumor cells into the lymphatic and blood circulations. As cancer cells are disseminated throughout the body, the patient’s response to the incision also causes an increase in local and systemic levels of growth factors, which may promote local recurrence and metastatic growth. The removal of the

Improved quality of anesthesia and cancer recurrence studies.

To the Editor While we applaud the conclusion of Durieux’s editorial1 suggesting that the best anesthesia practice in patients with cancer includes regional anesthesia, opioid reduction, and strategies supporting a decreased inflammatory response, we wish to express concern that data describing vital markers of cancer progression in the multitude of retrospective studies examining variations in anesthesia practice on cancer outcomes have been omitted. The American Joint Committee on Cancer (AJCC) group tumor-specific clinical outcome (survival) categories to provide prognostic categories that incorporate pathological variables beyond tumor-node-metastasis classification.2 For example, within the four broad disease stages of gastric cancer, a patient with “T1” disease but cancer infiltration of seven regional lymph nodes (Stage II, 4-year survival 50%) has a substantially more favorable prognosis than someone with invasive “T4b” disease without any nodal involvement (Stage III, 4-year survival 17%).3 The conclusions of studies examining associations between proposed interventions (such as a perioperative epidural) and clinical outcomes are hence significantly limited if AJCC staging is not used to determine specific tumor stage influence. The study by Myles et al.4 referenced by Dr. Durieux is an example of a study that examined for an association of effect of epidural and omitted AJCC stage classification. Six cancer groups were included in this study with consequent vast variation in recurrence patterns. Furthermore, the pathological variable of lymphovascular space invasion (LVSI) is not controlled for in many retrospective analyses. LVSI is a binary classification on the appearance (or not) of tumor invasion into adjacent lymphovascular structures—a prerequisite for metastatic spread. Considered a strong marker of “tumor aggression,” it predicts cancer recurrence following resection of gastric,5 prostate,6 esophageal,7 colon,8 ovarian,9 breast,10 endometrial,11 and cervical12 cancers. Scant data on LVSI status are presented in any of the studies referenced by Dr. Durieux; we feel that any analysis not including such indices overlooks important predictors of cancer recurrence and survival. In a recent study of perioperative epidural analgesia and cancer recurrence following gastroesophagectomy, we reported, on univariate analysis, the very strong association of LVSI with recurrence (hazard ratio 10.36, 3.70–29.02, P < 0.0001) compared with the influence of an epidural (hazard ratio 0.59, 0.32–1.09, P < 0.10).13 Only after controlling for LVSI using multivariate analysis was the association of benefit for an epidural on cancer outcomes revealed (hazard ratio 0.33, 0.17–0.63, P < 0.0001). Subgroups of patients with more aggressive disease (LVSI positive) may derive particular cancer benefit from epidural analgesia. While we await prospective studies of anesthetic technique on cancer recurrence, we would urge that future minor, appropriate acknowledgment may consist of cited references to the sections containing the work. We question the value of footnotes (used in the case of both our anonymous authors’ plagiarized chapters) that do not define what “a portion” means. Lam1 also is quite correct that “new authors copying from existing chapters without prior permission or shared authorship is never acceptable,” and as echoed by Moon and Camporesi,2 “portions of a previous chapter that are directly copied should be cited and referenced in the bibliography” and, we would add, surrounded with quotation marks. As stated in our Open Mind article,4 Harvard Medical School’s Guidelines for Editors and Authors of Medical Textbooks provide an example of how such issues may be resolved before publication. Wiwanitkit3 suggests several factors including inexperience, lack of concern, and differences in local culture as reasons that some so-called developing countries adhere to a different ethic when it comes to punishing or chastising those accused of plagiarism and/or other forms of scientific misconduct.5,6 Whether true or not, we adamantly believe that in the case of plagiarism, irrespective of economics, culture, or interest, only 1 standard must apply if science and truth and respect for academic institutions are to prevail. Wiwanitkit3 also commented that our article’s anonymous authorship was motivated by our concern for retaliation against the “whistleblowers.” While a reasonable assumption, identifying our 2 authors would have in turn identified the plagiarizers, as well as the book editors. This might have resulted in adverse academic decisions and distracted readers from our principal intent—to educate and prevent recurrences rather than retaliate. Finally, we have gratifying evidence of progress, as editors of 2 of the leading multiauthored anesthesia textbooks have informed us that as a result of our article, the next editions of each textbook will adopt our recommendations including scanning of each chapter for plagiarism and providing proper attribution to previous chapter authors if significant portions of the earlier chapters are included in the later versions.

Perioperative Biologic Perturbation and Cancer Surgery: Targeting the Adrenergic-Inflammatory Response and Microcirculatory Dysregulation

Many of the physiological responses that comprise the surgical stress response are known to promote cancer-signaling pathways. Tissue resection and exposure to the pharmaco-physiological stressors of anesthesia required for surgery activate local and systemic inflammatory cytokines, up-regulate cyclooxygenase with increased prostaglandin production, and increase adrenergic activity. The activation of neuro-hormonal pathways is increasingly linked with cancer propagation. Retrospective evidence suggests that the use of anesthetic techniques and adjuncts that modulate these pathways and commonly available to practicing anesthesiologists may benefit patients scheduled for cancer surgery. Minimising the inflammatory response, preventing perioperative immunosuppression, and optimizing fluid delivery may have oncological benefits (improved disease free survival, reduced postoperative complications with timely delivery of adjuvant therapies) that extend beyond enhanced postoperative recovery. This review will consider key components of local and systemic inflammatory response, relevant immune cell mediators, perioperative endothelial dysfunction, and relevant perioperative therapies specific to the care of the patient receiving cancer surgery.

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.

Improving trial design in cancer anesthesia (onco-anesthesia) research

To the Editor, Adrenergic and inflammatory pathways are increasingly implicated in cancer progression and, because of their perioperative up-regulation, are hypothesized to have an adverse effect on long-term postoperative outcomes. Our recent prospective, randomized trial investigated whether perioperative celecoxib modified the inflammatory response following major intra-cavity cancer surgery. The primary endpoint of the study was prostaglandin E metabolite (PGEM), a biomarker of cyclooxygenase activity. The methodology, results, and analytical techniques may be found in the original manuscript. Here, we report a post hoc analysis examining the influence of neoadjuvant chemotherapy (NCT), administered within three months preoperatively, on patients’ preoperative inflammatory state and on celecoxib’s impaired effectiveness perioperatively. These findings provide separate learning points with respect to the trial design and analysis in onco-anesthesia research. Patients undergoing NCT (n = 10) compared with NCT-naı̈ve patients (n = 19) had an increased preoperative PGEM (median [interquartile range], 30.3 [25.3-33.6] vs 21.9 [17.3-26.1] pg mL, respectively; between-group difference, 8.4 pg mL; 95% confidence interval, 3.15 to 12.6, P\ 0.003). This difference suggests that patients undergoing NCT are in a persistent preoperative pro-inflammatory state. Furthermore, the subgroup of NCT patients given perioperative celecoxib (n = 6) had persistently elevated postoperative PGE levels compared with those of the NCT-naı̈ve patients (n = 9; P = 0.03). The NCT-naı̈ve patients randomly assigned to celecoxib had smaller changes from baseline in prostaglandin levels at six, 24 and 48 hr following surgical incision compared to NCT patients (six hr: -4.1 vs 7.7 pg mL, P\ 0.001; 24 hr: -6.3 vs 5.5 pg mL, P\ 0.001; 48 hr: -6.7 vs 8.0 pg mL, P\ 0.03) (Figure). These data likely reflect an inability of celecoxib (administered at standard dosage) to inhibit the inflammatory response to surgery following NCT. This observation is supported by reports that chemotherapy dysregulates the post-translational modification of cyclooxygenase and leads to non-steroidal antiinflammatory drug (NSAID) resistance in patients on palliative chemotherapy regimens. The limitations of study size and post hoc analyses are appreciated, and over-interpretation of these data must be avoided. Nevertheless, we wish to convey that – given the escalation in research on the impact of anesthesiology techniques and adjuvants (e.g., NSAIDs, b-blockers) on long-term cancer outcomes – researchers designing future studies should not only consider American Joint Registration Trial Registry Number: ACTRN12615000041550; anzctr.org.au