**4. Perioperative factors that potentiate or inhibit immune responses**

During surgical procedures, there are multiple factors related to surgery that determine secondary depression of immunity. Within these, we find psychological stress, tissue damage typical of the surgical act, pain, hypothermia, blood transfusion and factors related to the drugs used that generate alterations in immunity [3-5].

## **4.1 Non-pharmacological perioperative factors**

### *4.1.1 Perioperative psychological stress*

The psychological stress of the patient who is going to undergo surgery can contribute to producing immunological alterations. This happens through sustained activation of the sympathetic nervous system (SNS) and the hypothalamus-pituitary–adrenal axis (HPA). The perioperative activation of the HPA axis will determine the release of adrenocorticotropic hormone (ACTH) and cortisol, which will result in the release of glucocorticoids from the cortex of the adrenal glands with the consequent immunosuppressive effect; as well as an increase in the secretion of plasma catecholamines, adrenaline, and noradrenaline. The latter seem to be the key biomarkers in the relationship between stress and cancer progression [18]. The protumoral effect secondary to the elevation of plasma levels of catecholamines has been attributed to the fact that some tumors express β1 and β2 adrenergic receptors on tumor cells, which favor cell migration, angiogenesis and impair cellular immunity. This cellular immune depression begins preoperatively and can last for several days after surgery [19]. Bartal et al. found that the number of CD8+ T lymphocytes and CD4+ T lymphocytes was lower in patients in the hours prior to surgery compared to patients who were not going to undergo surgical procedures [16].

## *4.1.2 Surgical act*

Surgery is the most effective treatment for cancer, but it is usually associated with systemic release of tumor cells. Tumor manipulation during resection may result in a "spill" of tumor cells into the bloodstream and lymphatic vessels. On the other hand, after surgery, the balance between pro- and antiangiogenic factors is shifted towards angiogenesis to facilitate tissue healing, which may favor tumor recurrence, metastasis formation, and activation of latent micrometastases [5]. The implantation of distant metastases focuses on the so-called "seed and soil" hypothesis; (seed and fertile land) described more than 100 years ago. It tries to explain the non-random location of the metastases of a primary tumor so that only certain tumor cells have the ability to colonize certain organs that have a suitable microenvironment for their growth [20]. It is known that the less aggressive the surgical trauma, the better preservation of the perioperative immune function, and therefore, the greater the trauma, the greater the probability of tumor recurrence; This is why it is proposed in some studies that the reduction of surgical trauma through the laparoscopic technique could reduce the probability of tumor recurrence in cancer patients [21, 22]. As previously mentioned, the surgical act encompasses multiple factors that favor tumor progression and dissemination. Among them, we highlight inadequate pain management, tissue injury related to surgery, hypothermia, and the need for transfusion of blood products.

### *4.1.3 Pain*

Acute pain results in suppression of NK cell activity. It is a powerful stimulant of the HPA axis and its poor perioperative management could be of great importance in favoring tumor recurrence. Optimal pain control can attenuate postoperative immunosuppression and, therefore, tumor recurrence [3, 13, 14, 19, 23]. Postoperative pain in patients undergoing bone tumor resection surgery is significant. Chung et al. [24] examined pain patterns in the postanesthetic recovery unit and found that orthopedic patients had the highest incidence of pain in the outpatient setting. There are many approaches to postoperative pain management, each of which must be tailored to the patient's pre- and postoperative course. Cancer patients often have pain prior to their surgery and may also be receiving significant amounts of opioids to control it. We must have an accurate idea of our patient's tolerance and opioid requirements, and we must plan accordingly.

### *4.1.4 Hypothermia*

Hypothermia can also influence the patient's immune system with the consequent impact on tumor recurrence. Impairs immune functions related to granulocyte chemotaxis and phagocytosis; as well as interfering with the production of antibodies [25]. An inhibition of the oxidative immune response on bacteria and a decrease in the phagocytic capacity of neutrophils and the generation of oxidative reaction intermediates have also been observed, in addition to exacerbating the immunosuppressive effects of surgery. Probably, the immunosuppressive effect of hypothermia is triggered by sympathetic discharge and consequent adrenal release of catecholamines, noradrenaline, and adrenaline, determining suppression of NK cells. Therefore, we believe that temperature monitoring, as well as the adoption of perioperative warming measures, will be extremely beneficial [26].

It has been shown that hypothermia increases the risk of requiring blood transfusions due to bleeding secondary to coagulopathies and platelet dysfunction; this is determinant of immunomodulation [17].

### *4.1.5 Perioperative transfusion of blood products*

Perioperative anemia is present in 2575% of cancer patients who are going to undergo surgery and is an independent risk factor for morbidity and mortality [27]. Tumors are relatively vascular structures and are therefore prone to bleeding throughout the intraoperative period. Metastases from kidney tumors and thyroid cancers cause significant neovascularization and can bleed dramatically during surgery, much more than other types of bone metastases. Optimizing preoperative hemoglobin values is of vital importance when it comes to reducing the need for transfusion of blood products [28].

Immunosuppression associated with blood transfusion is known in the literature as TRIM (transfusion-associated-immunomodulation) [29]. The effect of transfusion on immunity was suspected due to the better evolution of patients who underwent kidney transplantation and who had been transfused with more than 10 units of blood intraoperatively compared to patients who had not been transfused. In the transfused patients, the viability of the transplant was frankly higher [30]. Blood transfusions are associated with a reduction in Th cells and NK cells and a reduction in the production of cytokines, including IL-2 and IFN-γ [31]. Amato et al. [32] showed in a metaanalysis that perioperative blood transfusion was an independent risk factor for colorectal cancer recurrence.
