Impact of laparoscopic versus open surgery on humoral immunity in patients with colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Laparoscopic surgery (LS) is hypothesized to result in milder proinflammatory reactions due to less severe operative trauma, which may contribute to the observed clinical benefits after LS. However, previous systematic reviews and meta-analyses on the impact of LS on immunocompetence are outdated, limited and heterogeneous. Therefore, the humoral response after laparoscopic and open colorectal cancer (CRC) resections was evaluated in a comprehensive systematic review and meta-analysis. METHODS: Included were randomized controlled trials (RCTs) measuring parameters of humoral immunity after LS compared to open surgery (OS) in adult patients with CRC of any stage. MEDLINE, Embase, Web of Science (SCI-EXPANDED), Cochrane Library, Google Scholar, ClinicalTrials.gov and ICTRP (World Health Organization) were systematically searched. Risk of bias (RoB) was assessed using the Cochrane RoB2 tool. Weighted inverse variance meta-analysis of mean differences was performed for C-reactive protein (CRP), interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)α and vascular endothelial growth factor (VEGF) using the random-effects method. Methods were prospectively registered in PROSPERO (CRD42021264324). RESULTS: Twenty RCTs with 1131 participants were included. Narrative synthesis and meta-analysis up to 8 days after surgery was performed. Quantitative synthesis found concentrations to be significantly lower after LS at 0-2 h after surgery (IL-8), at 3-9 h (CRP, IL-6, IL-8, TNFα) and at postoperative day 1 (CRP, IL-6, IL-8, VEGF). At 3-9 h, IL-6 was notably lower in the LS group by 86.71 pg/ml (mean difference [MD] - 86.71 pg/ml [- 125.05, - 48.37], p < 0.00001). Combined narratively, 13 studies reported significantly lower concentrations of considered parameters in LS patients, whereas only one study reported lower inflammatory markers (for CRP and IL-6) after OS. CONCLUSION: The increase in postoperative concentrations of several proinflammatory parameters was significantly less pronounced after LS than after OS in this meta-analysis. Overall, the summarized evidence reinforces the view of a lower induction of inflammation due to LS.

Associations between intraoperative nociceptive response index and early postoperative acute kidney injury in patients undergoing non-cardiac surgery under general anesthesia: a single-center retrospective cohort study.

Both tissue hypoperfusion and elevated surgical stress during surgery are involved in the pathogenesis of postoperative acute kidney injury (AKI). Although intraoperative hypotension, which evokes renal hypoperfusion, has been reported to be associated with the development of postoperative AKI, there is no consensus on the association between surgical stress responses (e.g., hypertension and inflammation) and postoperative AKI. Given that intraoperative values of nociceptive response (NR) index are reportedly associated with surgical stress responses, the present study was performed to assess associations between intraoperative NR index and postoperative AKI in patients undergoing non-cardiac surgery. In this single-institutional retrospective cohort study, data of the highest and lowest values of NR index during surgery were obtained in consecutive adult patients undergoing non-cardiac surgery under general anesthesia from February 2022 to August 2023. Data on highest and lowest mean blood pressure (MBP) during surgery were also obtained. In 5,765 patients enrolled, multivariate regression analysis revealed that the development of early postoperative AKI was significantly associated with highest NR during surgery ≥ 0.920, lowest MBP during surgery < 54 mmHg, age ≥ 48 years, male sex, ASA-PS ≥ III, emergency, and duration of surgery ≥ 226 min. In addition to intraoperative hypotension, a higher level of intraoperative NR index is likely associated with higher incidence of early postoperative AKI in adult patients undergoing non-cardiac surgery under general anesthesia.

[Prospective analysis of inflammatory markers and perioperative clinical data in children with craniosynostosis undergoing reconstructive surgery]. / Prospektivnyi analiz dinamiki laboratornykh markerov vospaleniya i klinicheskoi kartiny perioperatsionnogo perioda pri rekonstruktivnykh operatsiyakh u detei s kraniosinostozami.

BACKGROUND: Craniosynostosis (CS) is a group of skull malformations manifested by congenital absence or premature closure of cranial sutures. Reconstructive surgery in the second half of life is traditional approach for CS. The issues of surgical stress response after reconstructive surgery for CS in children are still unclear. OBJECTIVE: To evaluate clinical and laboratory parameters in children undergoing traumatic reconstructive surgery for CS. MATERIAL AND METHODS: Inclusion criteria were CS, reconstructive surgery, age <24 months, no comorbidities and available laboratory diagnostic protocol including complete blood count, biochemical blood test with analysis of C-reactive protein, procalcitonin, ferritin and presepsin. The study included 32 patients (24 (75%) boys and 8 (25%) girls) aged 10.29±4.99 months after surgery between October 2021 and June 2022. Non-syndromic and syndromic forms of CS were observed in 25 (78.1%) and 7 (21.9%) cases, respectively. RESULTS: There were no infectious complications. We analyzed postoperative clinical data, fever, clinical and biochemical markers of inflammation. CONCLUSION: Early postoperative period after reconstructive surgery for CS in children is accompanied by significant increase of inflammatory markers (C-reactive protein, procalcitonin, ferritin). However, these findings do not indicate infectious complications. This is a manifestation of nonspecific systemic reaction. Severity of systemic inflammatory response syndrome with increase in acute phase proteins indicates highly traumatic reconstructive surgery for CS in children. Analysis of serum presepsin allows for differential diagnosis between infectious complication and uncomplicated course of early postoperative period.

[Prospective assessment of surgical stress response in patients with craniosynostosis: comparison of clinical and laboratory data]. / Prospektivnaya otsenka vyrazhennosti khirurgicheskogo stress-otveta u patsientov s kraniosinostozami: sopostavlenie klinicheskikh i laboratornykh dannykh.

BACKGROUND: Highly traumatic surgical correction of craniosynostosis (CS) is usually followed by severe postoperative period and high risk of complications. Surgical stress response (SSR) is an important and often neglected cause of severe early postoperative period. OBJECTIVE: To compare clinical and laboratory parameters of SSR in children who underwent various surgeries for CS. MATERIAL AND METHODS: The study included 63 patients aged 7.02±4.12 months. All ones underwent surgery for CS between October 2021 and June 2022. We analyzed clinical and laboratory markers of SSR, as well as correlation with severity of surgical stress. RESULTS: No surgical complications were observed. There were postoperative complications in 12 (19.0%) cases including febrile fever in 9 (14.3%) patients, severe pain and edematous syndromes with prolonged hospital-stay in 3 (4.8%) cases. Significant correlations were revealed between severity of surgical stress and certain laboratory markers (CRP, ACTH, T3, insulin, HOMA-IR). The last ones characterized SSR severity. Patients with high scores of stress response demonstrated more severe course of early postoperative period. CONCLUSION: Surgical stress scale makes it possible to predict early postoperative period and optimize patient management. Lower severity of surgical stress response following endoscopic interventions is another reason for the wider use of low-traumatic surgical methods in pediatric neurosurgery.

The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma.

Surgery remains to be the mainstay of treatment for hepatocellular carcinoma (HCC). Nonetheless, its therapeutic efficacy is significantly impaired by postoperative recurrence, which occurs in more than half of cases as a result of intrahepatic metastasis or de novo tumorigenesis. For decades, most therapeutic strategies on inhibiting postoperative HCC recurrence have been focused on the residual tumor cells but satisfying therapeutic outcomes are barely observed in the clinic. In recent years, a better understanding of tumor biology allows us to shift our focus from tumor cells toward the postoperative tumor microenvironment (TME), which is gradually identified to play a pivotal role in tumor recurrence. In this review, we describe various surgical stress and surgical perturbation on postoperative TME. Besides, we discuss how such alternations in TME give rise to postoperative recurrence of HCC. Based on its clinical significance, we additionally highlight the potential of the postoperative TME as a target for postoperative adjuvant therapeutics.

Major open abdominal surgery is associated with increased levels of endothelial damage and interleukin-6.

OBJECTIVE: To examine changes in biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress following major open abdominal surgery and the correlation to postoperative morbidity. INTRODUCTION: Major abdominal surgery is associated with high levels of postoperative morbidity. Two possible reasons are the surgical stress response and the impairment of the glycocalyx and endothelial cells. Further, the degree of these responses may correlate with postoperative morbidity and complications. METHODS: A secondary data analysis of prospectively collected data from two cohorts of patients undergoing open liver surgery, gastrectomy, esophagectomy, or Whipple procedure (n = 112). Hemodynamics and blood samples were collected at predefined timestamps and analyzed for biomarkers of glycocalyx shedding (Syndecan-1), endothelial activation (sVEGFR1), endothelial damage (sThrombomodulin (sTM)), and surgical stress (IL6). RESULTS: Major abdominal surgery led to increased levels of IL6 (0 to 85 pg/mL), Syndecan-1 (17.2 to 46.4 ng/mL), and sVEGFR1 (382.8 to 526.5 pg/mL), peaking at the end of the surgery. In contrast, sTM, did not increase during surgery, but increased significantly following surgery (5.9 to 6.9 ng/mL), peaking at 18 h following the end of surgery. Patients characterized with high postoperative morbidity had higher levels of IL6 (132 vs. 78 pg/mL, p = 0.007) and sVEGFR1 (563.1 vs. 509.4 pg/mL, p = 0.045) at the end of the surgery, and of sTM (8.2 vs. 6.4 ng/mL, p = 0.038) 18 h following surgery. CONCLUSION: Major abdominal surgery leads to significantly increased levels of biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress, with the highest levels seen in patients developing high postoperative morbidity.

Electroacupuncture Ameliorates Hypothalamic‒Pituitary‒Adrenal Axis Dysfunction Induced by Surgical Trauma in Mice Through the Hypothalamic Oxytocin System.

Electroacupuncture (EA) can effectively reduce surgical stress reactions and promote postoperative recovery, but the mechanisms remain unclear. The present study aims to examine the effects of EA on the hyperactivity of the hypothalamic‒pituitary‒adrenal (HPA) axis and investigate its potential mechanisms. Male C57BL/6 mice were subjected to partial hepatectomy (HT). The results showed that HT increased the concentrations of corticotrophin-releasing hormone (CRH), corticosterone (CORT), and adrenocorticotropic hormone (ACTH) in the peripheral blood and upregulated the expression of CRH and glucocorticoid receptors (GR) proteins in the hypothalamus. EA treatment significantly inhibited the hyperactivity of the HPA axis by decreasing the concentration of CRH, CORT, and ACTH in peripheral blood and downregulating the expression of CRH and GR in the hypothalamus. Moreover, EA treatment reversed the HT-induced downregulation of oxytocin (OXT) and oxytocin receptor (OXTR) in the hypothalamus. Furthermore, intracerebroventricular injection of the OXTR antagonist atosiban blocked the effects of EA. Thus, our findings implied that EA mitigated surgical stress-induced HPA axis dysfunction by activating the OXT/OXTR signaling pathway.

Physiological relationship between cardiorespiratory fitness and fitness for surgery: a narrative review.

Epidemiological evidence has highlighted a strong relationship between cardiorespiratory fitness and surgical outcomes; specifically, fitter patients possess heightened resilience to withstand the surgical stress response. This narrative review draws on exercise and surgical physiology research to discuss and hypothesise the potential mechanisms by which higher fitness affords perioperative benefit. A higher fitness, as indicated by higher peak rate of oxygen consumption and ability to sustain metabolic homeostasis (i.e. higher anaerobic threshold) is beneficial postoperatively when metabolic demands are increased. However, the associated adaptations with higher fitness, and the related participation in regular exercise or physical activity, might also underpin the observed perioperative benefit through a process of hormesis, a protective adaptive response to the moderate and intermittent stress of exercise. Potential mediators discussed include greater antioxidant capacity, metabolic flexibility, glycaemic control, lean body mass, and improved mood.

Effects of anesthetic depth on perioperative T lymphocyte subsets in patients undergoing laparoscopic colorectal cancer surgery: a prospective, parallel-controlled randomized trial.

BACKGROUND: During the perioperative period, the surgical stress response induced by surgical trauma tends to cause a decrease in peripheral lymphocytes. Anesthetics could reduce the stress response during surgery and prevent sympathetic nerve overexcitation. The goal of this study was to investigate how BIS-guided anesthetic depth affected peripheral T lymphocytes in patients undergoing laparoscopic colorectal cancer surgery. METHODS: A total of 60 patients having elective laparoscopic colorectal cancer surgery were randomly assigned and analyzed (n = 30 for deep general anesthesia, BIS 35, n = 30 for light general anesthesia, BIS 55). Blood samples were collected immediately before anesthesia induction and immediately after operation, 24 h and 5 days postoperatively. The CD4+/CD8 + ratio, T lymphocyte subsets (including CD3 + T cells, CD4 + T cells, and CD8 + T cells), and natural killer (NK) cells were analyzed by flow cytometry. Serum interleukin-6 (IL-6), interferon -É£ (IFN-É£), and vascular endothelial growth factor-α (VEGF-α) were also measured. RESULTS: The CD4+/CD8 + ratio decreased 24 h after surgery in two groups, but the reduction did not differ between the two groups (P > 0.05). The concentration of IL-6 and the numerical rating scale (NRS) score in the BIS 55 group were significantly higher than that in the BIS 35 group 24 h after surgery (P = 0.001). There were no intergroup differences in CD3 + T cells, CD4 + T cells, CD8 + T cells, NK cells, VEGF-α, or the IFN-É£. Statistical analyses showed no differences between the two groups in the incidence of fever and surgical site infection during hospitalization. CONCLUSIONS: Despite the fact that patients in deep general anesthesia group had low levels of the IL-6 24 h after surgery, the deep general anesthesia was not associated to a positive effect on patients' peripheral T lymphocytes during colorectal cancer surgery. We found no evidence that peripheral T lymphocyte subsets and natural killer cells were affected by the targeting a BIS of either 55 or 35 in patients undergoing laparoscopic colorectal cancer surgery in this trial. TRIAL REGISTRATION: ChiCTR2200056624 ( www.chictr.org.cn ).

A standardized anesthetic/analgetic regimen compared to standard anesthetic/analgetic regimen for patients with high-risk factors undergoing open lumbar spine surgery: a prospective comparative single-center study.

The objective of the study is to improve the results of patients undergoing lumbar spine surgery who are at high risk for anesthesia and/or surgical complications. Two independent groups were compared: the study group (SG, n = 40) (standardized neuroanesthetic protocol with multimodal analgesia) and the control group (CG, n = 40) (intravenous anesthesia based on propofol and fentanyl). The data were collected using prospective observation of early and long-term results of lumbar fusion. After 24 months, the level of functional state and quality of life were studied. Patients in the SG did not have statistically significant changes in intraoperative hemodynamics; the best indicators of cognitive functions were noted. The effectiveness of the SG compared with the CG was confirmed by a statistically significantly lower amount of perioperative opioid drugs required (p = 0.01) and a minimal level of incisional pain (p < 0.05). An intergroup comparison of the adverse effects of anesthesia revealed a significantly lower number in the SG (n = 4) compared to the CG (n = 16) (p = 0.004). The number of postoperative surgical complications was comparable (p = 0.72). Intergroup comparison showed improved ODI, SF-36, and the Macnab scale at 24 months after surgery in the SG compared to the CG (p < 0.05). Long-term clinical results correlated with the level of incisional pain in the first three postoperative days. Our standardized neuroanesthetic protocol ensured effective treatment of postoperative incisional pain, significantly decreased the perioperative use of opioids, reduced adverse anesthesia events, and improved long-term clinical results in patients with high risk factors for anesthetic complications who undergoing open lumbar spine surgery.

Strategies for optimal perioperative outcomes in gastric cancer.

Cancer and surgery represent a major stress on the human body. Any condition that prevents patients from tolerating the physiological stress is a risk factor for poor outcome. There is a need to identify these impairments early in the process with a simple screening, followed by assessments that provide a holistic picture of the patient. The proposed path of multimodal prehabilitation acts synergistically with enhanced recovery after surgery care to achieve optimal patient outcomes.

Perioperative changes in cell-free DNA for patients undergoing surgery for colon cancer.

BACKGROUND: Various conditions with cellular decay are associated with elevated cell-free DNA (cfDNA). This study aimed to investigate if perioperatively measured cfDNA levels were associated with the surgical approach, complications, or recurrence. METHODS: Plasma was obtained from patients who underwent surgery for colon cancer at admission and at the time of discharge. Quantitative measurement of cfDNA was performed by amplifying two amplicons of 102 base pairs (bp) and 132 bp of Beta-2-Microglobulin (B2M) and Peptidyl-Prolyl cis-trans Isomerase A (PPIA), respectively. RESULTS: cfDNA was measured in 48 patients who underwent surgery for colonic cancer. Sixteen patients had recurrence during the follow-up period, fifteen developed a postoperative complication, and seventeen patients developed neither, acting as the control group. Postoperative cfDNA levels were significantly elevated from baseline samples, across all groups, with a median preoperatively B2M level of 48.3 alleles per mL and postoperatively of 220 alleles per mL and a median preoperatively level PPIA of 26.9 alleles per mL and postoperatively of 111.6 alleles per mL (p < 0.001 for B2M and p < 0.001 for PPIA). Postoperative levels of PPIA, but not B2M, were significantly higher in patients experiencing complications than in the control group (p = 0.036). However, a tendency towards an association between the surgical approach and the changes in cfDNA levels was found for PPIA (p = 0.058), and B2M (p = 0.087). CONCLUSIONS: Plasma cfDNA was increased after surgery in all patients with colon cancer. Postoperative PPIA levels were significantly higher in patients experiencing surgical complications but not in B2M levels.

Surgical Stress and Cancer Progression: New Findings and Future Perspectives.

PURPOSE OF REVIEW: The stress response to surgery is essential for maintaining homeostasis and exhibits anti-tumor effects; however, an ongoing and exaggerated stress response may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between surgical stress and cancer progression. RECENT FINDINGS: Surgical stress exhibits both anti-tumor and cancer-promoting effects by causing changes in the neuroendocrine, circulatory, and immune systems. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although surgical stress may have anti-tumor effects, it is necessary to inhibit an excessive stress response, mostly showing cancer-promoting effects.

Evaluation of the systemic inflammatory response, endothelial cell dysfunction, and postoperative morbidity in patients, receiving perioperative corticosteroid, developing severe mesenteric traction syndrome - an exploratory study.

OBJECTIVE: To determine whether a severe mesenteric traction syndrome (MTS) leads to increased surgical stress, endothelial dysfunction, and postoperative morbidity in a cohort in which all patients received a single dose of methylprednisolone. INTRODUCTION: Preoperatively administered corticosteroids lower the incidence of severe MTS and may also attenuate surgical stress and endothelial damage associated with the development of severe MTS, ultimately lowering the postoperative morbidity. METHODS: This exploratory study analyzed prospectively collected data from 45 patients all receiving 125 mg methylprednisolone. No control group was included. The severity of MTS was graded intraoperatively, and postoperative morbidity was assessed blinded. Blood samples for plasma prostacyclin (PGI2), IL6 and endothelial damage (Syndecan-1, sVEGRF1 and sThrombomodulin) biomarkers were obtained at predefined time points. RESULTS: Patients undergoing either open liver surgery (n = 23) or Whipple's procedure (n = 22) were included. No differences were found in postoperative morbidity between patients developing and not developing severe MTS. Surgery led to significantly increased plasma levels of biomarkers indicative of surgical stress and endothelial damage. Further, patients developing severe MTS had increased levels of PGI2 (p = 0.05) and lower systemic vascular resistance (p < 0.05) 15 min into surgery. However, when comparing the biomarkers of surgical stress, endothelial damage no differences between patients with and without severe MTS were identified. CONCLUSION: This exploratory study found that surgery was associated with a pro-inflammatory response and damage to the endothelium. However, no differences were found between patients developing severe MTS and patients developing moderate/no MTS in biomarkers of surgical stress, endothelial damage, or postoperative morbidity. Corticosteroids may therefore attenuate the endothelial damage in patients developing severe MTS. However, as this was an exploratory study, these findings must be confirmed in future randomized controlled studies.

Severe mesenteric traction syndrome is associated with increased systemic inflammatory response, endothelial dysfunction, and major postoperative morbidity.

This study aimed to determine if mesenteric traction syndrome (MTS) triggers increased systemic inflammation and endothelial cell dysfunction. Patients developing severe MTS had pronounced early IL6 elevations followed by endothelial cell damage. Furthermore, these processes were associated with increased postoperative morbidity. OBJECTIVE: To determine whether mesenteric traction syndrome (MTS) leads to increased systemic inflammation and dysfunction of the glycocalyx and endothelial cell and whether this correlates with the degree of postoperative morbidity. INTRODUCTION: Severe MTS is associated with increased postoperative morbidity following major gastrointestinal surgery, but the pathophysiological mechanism has not been previously explored. Systemic inflammatory response and impaired glycocalyx and endothelial cells may be responsible for the development of symptoms. METHODS: The study analyzed prospectively collected data from two cohorts (n = 67). The severity of the MTS response was graded intraoperatively and blood samples for PGI2, catecholamines, IL6, and endothelial biomarkers obtained at predefined time points. RESULTS: Patients undergoing either esophagectomy (n = 45) or gastrectomy (n = 22) were included. Surgery led to significantly increased plasma concentrations of all biomarkers. Yet, patients who developed severe MTS had higher baseline epinephrine levels (p < 0.05) and higher levels of PGI2 (p < 0.05), Syndecan-1 (p < 0.001), and sVEGFR1 (p < 0.001). Peak values of IL6, Syndecan-1, sVEGFR1, and sTM all correlated to peak PGI2. Lastly, patients with high postoperative morbidity had higher baseline epinephrine (p = 0.009) and developed higher plasma IL6 (p = 0.007) and sTM (p = 0.022). CONCLUSION: The development of severe MTS during upper gastrointestinal surgery is associated with preoperative elevated plasma epinephrine and further a more pronounced proinflammatory response and damage to the vascular endothelium. The increased postoperative morbidity seen in patients with severe MTS may thus, in part, be explained by an inherent susceptibility towards an inappropriate secretion of PGI2, which leads to an increased surgical stress response and endothelial damage. These findings must be confirmed in a new prospective cohort.

Comparison of postoperative cytokine and hormone between endoscopically assisted and open parotid tumor resection.

OBJECTIVE: Endoscopically assisted extracapsular dissection through a single incision along the cephaloauricular furrow has been adapted as a method of access for operating on benign parotid gland tumors. However, no study has compared the immune and stress responses after surgery between the endoscopic procedure and conventional open surgery. METHODS: Through a randomized method, 50 patients with benign parotid gland tumors were assigned to undergo either endoscopically assisted extracapsular dissection or open parotidectomy. The postoperative inflammatory changes and hormonal response in the patients were analyzed at serum level during the preoperative period and at 12, 24, and 72 hr after either surgery. RESULTS: Twenty-three patients received an endoscopic procedure, while 27 underwent open surgery. The size of the incision, amount of intraoperative bleeding, volume of drainage, postoperative pain score, and satisfaction with appearance were all improved in the endoscopic procedure group. Additionally, the serum levels of C-reactive protein, interleukin (IL)-6, IL-10, and cortisol were significantly lower in the endoscopy group in comparison with those in the open surgery group. CONCLUSION: Endoscopically assisted extracapsular dissection on patients with benign parotid gland tumors is associated with lower inflammatory changes and hormone responses than open surgery, thereby reducing perioperative pathophysiological disturbance and enhancing recovery after surgery.

Systemic inflammatory response in robot-assisted and laparoscopic surgery for colon cancer (SIRIRALS): study protocol of a randomized controlled trial.

BACKGROUND: Robot-assisted surgery is being increasingly adopted in treating colorectal cancer, and the transition from laparoscopic surgery to robot-assisted surgery is a trend. The evidence of the benefits of robot-assisted surgery is sparse. However, findings are associated with improved patient-related outcomes and overall morbidity rates compared to laparoscopic surgery. This induction is unclear, considering both surgical modalities are characterized as minimally invasive. This study aims to evaluate the systemic and peritoneal inflammatory stress response induced by robot-assisted surgery compared with laparoscopic surgery for elective colon cancer resections in a prospective, randomized controlled clinical trial. METHODS: This study is a single-centre randomized controlled superiority trial with 50 colon cancer participants. The primary endpoint is the level of systemic inflammatory response expressed as serum C-reactive protein (CRP) and interleukin 6 (IL-6) levels between postoperative days one and three. Secondary endpoints include (i) levels of systemic inflammation in serum expressed by a panel of inflammatory and pro-inflammatory cytokines measured during the first three postoperative days, (ii) postoperative surgical and medical complications (30 days) according to Clavien-Dindo classification and Comprehensive Complication Index, (iii) intraoperative blood loss, (iv) conversion rate to open surgery, (v) length of surgery, (vi) operative time, (vii) the number of harvested lymph nodes, and (viii) length of hospital stay. The exploratory endpoints are (i) levels of peritoneal inflammatory response in peritoneal fluid expressed by inflammatory and pro-inflammatory cytokines between postoperative day one and three, (ii) patient-reported health-related quality of recovery-15 (QoR-15), (iii) 30 days mortality rate, (iv) heart rate variability and (v) gene transcript (mRNA) analysis. DISCUSSION: To our knowledge, this is the first clinical randomized controlled trial to clarify the inflammatory stress response induced by robot-assisted or laparoscopic surgery for colon cancer resections. Trial registration This trial is registered at Clinicaltrials.gov (Identifier: NCT04687384) on December, 29, 2020, Regional committee on health research ethics, Region of Southern Denmark (N75709) and Data Protection Agency, Hospital Sønderjylland, University Hospital of Southern Denmark (N20/46179).

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery.

The physiological stress response to surgery promotes wound healing and functional recovery and includes the activation of neural, inflammatory and proangiogenic signaling pathways. Paradoxically, the same pathways also promote metastatic spread and growth of residual cancer. Human and animal studies show that cancer surgery can increase survival, migration and proliferation of residual tumor cells. To secure the survival and growth of disseminated tumor cells, the formation of premetastatic niches in target organs involves a complex interplay between microenvironment, immune system, circulating tumor cells, as well as chemical mediators and exosomes secreted by the primary tumor. This review describes the current understanding of the early mechanisms of dissemination, as well as how surgery may facilitate disease progression.

Suppression of behavioral activity and hippocampal noradrenaline caused by surgical stress in type 2 diabetes model mice.

BACKGROUND: There has been much discussion recently about the occurrence of neuropsychological complications during the perioperative period. Diabetes is known to be one of the metabolic risk factors. Although the number of patients with diabetes mellitus (DM) has been increasing, the pathophysiology of postoperative neuropsychological dysfunction in DM patients is still unclear. Recently, a deficiency of neurotransmitters, such as monoamines, was reported to be associated with mental disorders. Therefore, we investigated the effects of surgical stress on behavioral activity and hippocampal noradrenaline (NA) level in type 2 diabetes mellitus model (T2DM) mice. METHODS: Eighty-four 6-week-old male C57BL/6J mice were divided into four groups (non-diabetes, non-diabetes with surgery, T2DM, and T2DM with surgery groups). T2DM mice were established by feeding a high-fat diet (HFD) for 8 weeks. At 14 weeks of age, fifteen mice in each group underwent a series of behavioral tests including an open field (OF) test, a novel object recognition (NOR) test and a light-dark (LD) test. In the surgery groups, open abdominal surgery with manipulation of the intestine was performed 24 h before the behavioral tests as a surgical stress. Hippocampal noradrenaline (NA) concentration was examined in six mice in each group by high-performance liquid chromatography. The data were analyzed by the Mann-Whitney U test, and p values less than 0.05 were considered significant. RESULTS: The T2DM group showed significantly increased explorative activity in the NOR test (P = 0.0016) and significantly increased frequency of transition in the LD test (P = 0.043) compared with those in the non-diabetic group before surgery. In T2DM mice, surgical stress resulted in decreased total distance in the OF test, decreased explorative activity in the NOR test, and decreased frequency of transition in the LD test (OF: P = 0.015, NOR: P = 0.009, LD: P = 0.007) and decreased hippocampal NA (P = 0.015), but such differences were not observed in the non-diabetic mice. CONCLUSIONS: Mice with T2DM induced by feeding an HFD showed increased behavioral activities, and surgical stress in T2DM mice caused postoperative hypoactivity and reduction of the hippocampal NA level.

CDX2 expression and perioperative patient serum affects the adhesion properties of cultured colon cancer cells.

BACKGROUND: Colon cancer is one of the most commonly diagnosed types of cancer with surgical resection of the tumor being the primary choice of treatment. However, the surgical stress response induced during treatment may be related to a higher risk of recurrence. The aim of this study was to examine the effect of surgery on adhesion of cultured colon cancer cells with or without expression of the tumour suppressor CDX2. METHOD: We enrolled 30 patients undergoing elective, curatively intended laparoscopic surgery for colon cancer in this study. Blood samples were drawn 1 day prior to surgery and 24 h after surgery. The samples of pre- and postoperative serum was applied to wild type colon cancer LS174T cells and CDX2 inducible LS174T cells and adhesion was measured with Real-Time Cell-Analysis iCELLigence using electrical impedance as a readout to monitor changes in the cellular adhesion. RESULTS: Adhesion abilities of wild type LS174T cells seeded in postoperative serum was significantly increased compared to cells seeded in preoperative serum. When seeding the CDX2 inducible LS174T cells without CDX2 expression in pre- and postoperative serum, no significant difference in adhesion was found. However, when inducing CDX2 expression in these cells, the adhesion abilities in pre- and postoperative serum resembled those of the LS174T wild type cell line. CONCLUSIONS: We found that the adhesion of colon cancer cells was significantly increased in postoperative versus preoperative serum, and that CDX2 expression affected the adhesive ability of cancer cells. The results of this study may help to elucidate the pro-metastatic mechanisms in the perioperative phase and the role of CDX2 in colon cancer metastasis.