Do Stress Responses Promote Leukemia Progression? An Animal Study Suggesting a Role for Epinephrine and Prostaglandin-E2 through Reduced NK Activity

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition

The role of perioperative adjuncts in cancer outcomes: beta-adrenergic receptor antagonists, NSAIDs and anti-fibrinolytics

The perioperative period of cancer surgery and its impact on patients’ long-term cancer outcomes is of increasing research interest. The physiological changes coincident with surgery are characterized by a stress response manifesting as activation of inflammatory pathways and immunosuppression. These changes are potentially deleterious to a patient’s capacity to control residual or released tumor cells. Of particular relevance to anesthesiologists is the role of available adjuncts that may offset these changes to improve patients' recovery from surgery and their long-term cancer outcomes. Animal and human evidence indicates a potential therapeutic benefit for β-adrenergic receptor antagonists, selective cyclooxygenase inhibitors, and anti-fibrinolytics administered through the perioperative period. In addition to reducing the surgical stress response, these agents may effect the cancer-host tissue interface to reduce cancer invasion and dissemination. Future research will focus on defining the role of these agents as integral perioperative adjuncts for cancer surgery

Immunotherapy during the Immediate Perioperative Period: A Promising Approach against Metastatic Disease

Tumor excision is a necessary life-saving procedure in most solid cancers. However, surgery and the days before and following it, known as the immediate perioperative period (IPP), entail numerous prometastatic processes, including the suppression of antimetastatic immunity and direct stimulation of minimal residual disease (MRD). Thus, the IPP is pivotal in determining long-term cancer outcomes, presenting a short window of opportunity to circumvent perioperative risk factors by employing several therapeutic approaches, including immunotherapy. Nevertheless, immunotherapy is rarely examined or implemented during this short timeframe, due to both established and hypothetical contraindications to surgery. Herein, we analyze how various aspects of the IPP promote immunosuppression and progression of MRD, and how potential IPP application of immunotherapy may interact with these deleterious processes. We discuss the feasibility and safety of different immunotherapies during the IPP with a focus on the latest approaches of immune checkpoint inhibition. Last, we address the few past and ongoing clinical trials that exploit the IPP timeframe for anticancer immunotherapy. Accordingly, we suggest that several specific immunotherapies can be safely and successfully applied during the IPP, alone or with supporting interventions, which may improve patients’ resistance to MRD and overall survival