Research ArticleClinical Studies
Open Access

Free Interleukin 18 (IL-18F) Blood Levels Following Midline Laparotomy: A Prospective Randomized Study of Patients With Benign Disease and Patients With Cancer

MAARET ESKELINEN, TUOMAS SELANDER, JUKKA PULKKINEN, KAI KAARNIRANTA, ESA HÄMÄLÄINEN and MATTI ESKELINEN
Anticancer Research February 2025, 45 (2) 667-675; DOI: https://doi.org/10.21873/anticanres.17454

Abstract

Background/Aim: The purpose of this work was to assess blood level correlations of free IL-18 (IL-18F) and various cytokines (CYTs), caspase-1 (Casp1), high sensitive C-reactive protein (hs-CRP), and 4-hydroxynonenal (4-HNE) in 56 patients subjected to midline laparotomy (MLa) and to investigate their link to pain scales. Patients and Methods: Blood levels of IL-18F and seven CYTs (IL-18, IL-18BP, IL-1ra, IL-6, IL-8, IL-10, IL-1β), Casp1, hs-CRP, and 4-HNE were measured and the pain surveys were reported using numerical rating scale (NRS) and the Brief Pain Inventory (BPI) scales conducted preoperatively (PRE) and postoperatively (POP). Results: The IL-18F levels decreased at POP and the decrease between POP1 (immediately after MLa) and POP2 (24 hours after MLa) blood levels (26.5 versus 20.0) was significant (p<0.001). Moreover, the IL-18F levels at POP2 were slightly higher in patients with cancer than in patients with benign disease (21.2 versus 17.8). Interestingly, the IL-18F levels correlated to IL-18 (r=0.523, p<0.001), IL-18BP (r=−0.475, p<0.001), and 4-HNE (r=0.414, p<0.001) levels. Furthermore, the IL-18F levels correlated with BPI score values (r=−0.459, p=0.05). Conclusion: This is the first report to demonstrate a link between increased IL-18F levels and pain scales in MLa. IL-18F levels decreased significantly after operation and correlated with IL-18, IL-18BP, and 4-HNE blood levels, and inversely correlated with BPI pain scores. These results support the applicability of acute phase response biomarkers in understanding pain in patients subjected to MLa.

Key Words:

Interleukin 18 (IL-18) is a proinflammatory cytokine (CYT) that belongs to the IL-1 family of ligands (1). Macrophages and dendritic cells are the primary sources for active IL-18, but the IL-18 precursor is expressed in epithelial cells throughout the body. IL-18 is synthesized as an inactive precursor requiring processing by caspase1 (Casp1) into an active CYT and the IL-18 precursor is present in nearly all cells in healthy humans (2, 3). The IL-18 receptor (IL-18R) complex consists of two receptor chains and the activity of IL-18 is balanced by the presence of an IL-18 binding protein (Il-18BP) (1-4). In humans, increased disease severity can be associated with an imbalance of IL-18 to IL-18BP, such that the blood levels of free IL-18 (IF-18F) are elevated (5). IL-18 activates signaling pathways, contributing to the production of chemokines, which play an important role in the recruitment of leukocytes at inflammatory sites and subsequently the development of acute phase inflammatory response (APR) (5, 6).

IL-18 was originally identified as an inflammation-induced CYT that is secreted by immune cells, while many studies have focused on non-inflammatory characteristics of IL-18 in energy homeostasis and neural stability (6, 7). Furthermore, IL-18 has been implicated in acute kidney injury, autoimmune diseases, emphysema, hemophagocytic syndromes, inflammatory bowel disease, macrophage activation syndrome (MAS), metabolic syndromes, myocardial function, psoriasis and sepsis, and in some diseases, IL-18 is a protective agent (5-10). In addition, IL-18 is reportedly required for lipid metabolism in the liver and brown adipose tissue (6). Furthermore, several groups have also sought to clarify the role of IL-18 and IL-18BP in the development of inflammation (4, 7-20). IL-18 together with IL-1β are key biomarkers of inflammasome activation (21). Inflammasomes are cytosolic multiprotein complexes that respond to various cellular stressors and induce CYT secretion. Active Casp1 is required to cleave the proforms of IL-1β and IL-18 into their mature and secreted bioactive forms. Oxidative stress and lipid peroxidation are well-known activators of inflammasomes (21).

The studies to date investigating the impact of IL-18/IL-18BP ratio on inflammation and pain risk have not considered IL-18F blood levels. Until now, the lack of measures has delayed the progress in the IL-18F blood level calculations. In the present study, we detected the variation in IL-18/IL-18BP blood levels, and we were therefore able to calculate the IL-18F blood levels in patients with midline laparotomy (MLa). The aim of this study was to investigate IL-18F blood levels and other biomarkers and their correlation to pain scales.

Patients and Methods

The patients with cancer (CA) or benign disease (BD) were randomized to the control group (n=11) and to one of the three rectus sheath block analgesia (RSB) groups; single dose (SiD) (n=12), repeated dose (ReD) (n=12) and continuous dose (CoD) (n=11) groups. Detailed description of the protocol is shown by Purdy et al. (22, 23) and in Figure 1 and in Table I.

Figure 1.
Figure 1.

Study flowchart.

View this table:
Table I.

The clinical data of the four study groups.

The blood samples were collected before surgery (PRE), immediately after surgery (POP1) and 24 hours post-operatively (POP2). The blood levels of IL-18F were determined by the law of mass action as described by Carbone et al. (9) and Novick et al. (10). The calculation was based on the following parameters: i) IL-18 and IL-18BP levels, determined using ELISA assays; ii) a 1:1 stoichiometry ratio for the complex IL-18/IL-18BP and iii) a dissociation constant K=0.4 nM. The molecular weight adopted for IL-18 and IL-18BP are 18.2 kDa and 38 kDa, respectively. The high-sensitivity C-reactive protein (hs-CRP), CYT, Casp1, and 4-hydroxynonenal (4-HNE) assays were detailed in previous reports (20, 22-24). Detailed description of the numeric rating scale (NRS) and Brief Pain Inventory (BPI) scoring is shown in earlier reports (22-25).

Baseline group comparisons in Table I were conducted using analysis of variance (ANOVA), the chi-square test, or Fisher’s exact test. The blood biomarker levels presented in Table II and Table III were analyzed using the Mann-Whitney U-test. A linear mixed-effects model (LME) was applied to assess group differences across time points and the overall group × time interaction effect. Spearman’s method was used to test for correlation between IL-18F concentrations and other biomarkers and pain scale values. Data were analyzed using IBM SPSS statistical software (IBM SPSS Statistics for Windows, version 26.0, IBM Corporation, Armonk, NY, USA).

View this table:
Table II.

Median (interquartile range) marker levels before (PRE), immediately after (POP1), and 24 hours after (POP2) surgery.

View this table:
Table III.

Median (interquartile range) marker levels before (PRE), immediately (POP1), and 24 hours post-operation (POP2) in all study patients.

Results

Before MLa, 56 patients were randomized according to the study protocol. However, blood samples for PRE, POP1, and POP2 were successfully obtained from 44 patients as per the protocol (Figure 1). The final study cohort of 44 patients included 15 patients with BD, and 29 patients with CA (Table I). RSB analgesia significantly improved patient satisfaction levels at 24 hours following operation (SFS24) as follows: control group, SiD group, ReD group, and CoD group (8; 9; 9.5, and 10, respectively, p=0.001, Table I).

The patients subjected to MLa in the control group had higher IL-18F levels preoperatively versus SiD, ReD, and CoD groups (median IL-18F; 32.3 versus 26.7, 24.9 and 26.7, respectively, Table II). In addition, the patients subjected to MLa in the control group had higher IL-18F POP levels versus patients in the SiD, ReD, and CoD groups (IL-18F at POP1; 29.5 versus 20.8, 25.9 and 25.9, respectively, Table II). Furthermore, there were no significant distinctions in other CYTs and hs-CRP levels between the control group and SiD, ReD, and CoD groups (Table II). The POP alteration of CYT and hs-CRP levels are shown in Table III. In all patients subjected to MLa, IL-18F levels decreased at POP1/POP2 and the POP2 decrease was statistically significant (p<0.001, Table III). In addition, IL-18 and IL-18BP levels decreased significantly at POP1 compared to PRE levels (p<0.001). However, IL-18 and IL-18BP levels increased at POP2, showing a significant time effect in the LME model (p<0.001).

The PRE, POP1, and POP2 IL-18 levels were higher in patients with CA versus patients with BE (177/137/182 versus 135/108/126, Table IV). However, there were no significant differences in IL-18F blood levels in patients with CA versus patients with BD (PRE/POP1/POP2; 26.8/26.3/21.2 versus 26.8/28.2/17.8, respectively, Table IV). The IL-18F versus IL-18 levels correlated significantly in patients subjected to MLa (r=0.523, p<0.001) (Figure 2). In addition, Il-18F levels correlated significantly to IL-18BP levels (r=−0.475 p<0.001) (Figure 3) and to 4-HNE levels (r=0.414, p<0.001) (Figure 4), while the correlation between IL-18F levels and CRP (r=−0.249), MDA (r=0.281), Casp1 (r=0.271), and IL-6 (r=−0.270) levels was not statistically significant. Interestingly, a significant correlation was observed between IL-18F levels (all time points) versus BPI pain scores one year following surgery in this study cohort (r=−0.459, p=0.05).

View this table:
Table IV.

Median (interquartile range) marker levels at different time points in patients with benign diseases (N=15) and in those with cancer (n=29).

Figure 2.
Figure 2.

Scatter plot of free IL-18 (IL-18F) blood levels versus IL-18 blood levels in patients subjected to midline laparotomy (MLa) (r=0.523, p<0.001).

Figure 3.
Figure 3.

Scatter plot of free IL-18 (Il-18F) blood levels versus IL-18BP blood levels in patients subjected to midline laparotomy (MLa) (r=−0.475, p<0.001).

Figure 4.
Figure 4.

Scatter plot of free IL-18 (Il-18F) blood levels versus 4-HNE blood levels in patients subjected to midline laparotomy (MLa) (r=0.414, p<0.05).

Discussion

In a previous study, Purdy et al. (23) investigated whether the RSB reduces the APR in patients with CA versus patients with BD. They measured blood levels of hs-CRP and five CYTs (IL-1ra, IL-6, IL-8, IL-10, IL-1β) at three time points; PRE, POP1, and POP2. The aim was to compare blood levels of the hs-CRP and CYTs in different RSB groups in patients with CA versus patients with BE. The patients in the CoD group had higher IL-10 blood levels at POP than the SiD/ReD/CoD groups (p=0.029). In addition, patients in the SiD/ReD/CoD groups combined had higher IL-10 POP1 blood levels than the control group (p=0.028). Furthermore, they found a significant correlation between the IL-10 blood levels versus NRS scores in all patients (r=0.40, p=0.03) and a significant correlation between the NRS scores and IL-1β levels in all patients (r=0.38, p=0.04). The Authors concluded that, although RSB does not reduce the blood levels of APR biomarkers, their study presents a novel finding: a correlation between NRS scores and IL-10 and IL-1β blood levels, proposing that APR and pain are associated. The same authors also studied a possible role of IL-18BP in adjustment of pain by APR and analgesics (18). The aim of their study was to assess IL-18BP levels in patients subjected to laparoscopic cholecystectomy (LC) and mini-cholecystectomy (MC) and to report their relationship with other CYTs and the number of analgesic doses (NAD). The levels of IL-18BP, six other CYTs (IL-18, IL-1ra, IL-6, IL-10, IL-1β, and IL-8) and hs-CRP were measured at PRE, POP1, and POP2 in 114 patients with cholelithiasis. They found that IL-18BP levels at POP correlated with NRS scores at 24 hours (r=0.194, p=0.009). Furthermore, the IL-18BP levels correlated with NAD counts (r=0.254, p<0.001). The authors deduced that IL-18BP correlates with NRS and NAD in patients subjected to LC and MC, suggesting a role for IL-18BP in adjusting POP pain by APR. The same authors assessed IL-18 and IL-18BP levels versus NRS pain scores in patients subjected to MLa (19). They measured levels of seven CYTs and hs-CRP at three time points; PRE, POP1, and POP2 in 56 patients subjected to MLa. The satisfaction of the patients 24 hours following surgery was recorded on an 11-point numeric rating scale (SFS24). They found that IL-18 and IL-18BP levels decreased at POP1, with a highly significant drop observed between PRE and POP1 levels (p<0.001). However, the hs-CRP, IL-18 and IL-18BP levels increased at POP2 (p<0.001) with the LME model showing a significant time effect (p<0.001). Furthermore, the PRE and POP2 IL-18 values were clearly higher in patients with CA versus those with BD (177/182 vs. 135/126, p=0.039/p=0.013, respectively). Interestingly, in all patients, there was a correlation between the IL-18 and IL-18BP levels at POP1 (r=0.315, p=0.036). The authors deduced that the correlation of IL-18BP with SFS24 (r=0.361, p=0.05) is a new discovery and is showing that APR and quality of life are associated.

Chalikias et al. (7) studied IL-18/IL-10 ratio versus adverse events in 107 consecutive patients with acute coronary syndrome (ACS). During hospitalization 44/107 patients with ACS (41%) had adverse events and 63/107 (59%) had no adverse events. In detection of adverse events, significantly higher risk prediction was found for IL-18/IL-10 ratio than single biomarkers (7). The authors concluded that blood IL-18/IL-10 ratio is an independent predictor of in-hospital adverse events in patients with ACS. They strongly suggest individual blood IL-18/IL-10 ratio measurement to assess whether patients admitted to hospital with ACS have enhanced risk for in-hospital adverse events (7).

Thompson et al. (8) assessed IL-18, IL-18BP, and IL-18F blood levels PRE and POP in 196 patients with coronary heart disease (CHD) following coronary artery bypass graft (CABG) operation. IL-18F blood levels peaked at six hours POP (PRE/POP; 117/331 pg/ml, respectively) and the POP (24 hours) IL-18F blood levels were significantly higher in those patients with CHD, who suffered a major complication following CABG surgery (125 versus 80 pg/ml, p<0.01). The authors concluded that blood levels of IL-18F could predict the outcome of patients with CHD following surgery.

Carbone et al. (9) studied IL-18, IL-18BP, and Il-18F blood levels in patients with pancreatic carcinoma (PaCa) following surgery and/or chemotherapy. The blood IL-18F levels correlated significantly with disease severity and poor survival. The blood levels of IL-18BP were unchanged following surgery, but IL-18F blood levels were enhanced POP. Gemcitabine combined with either 5-fluorouracil or oxaliplatin increased IL-18 and IL-18F blood levels without affecting IL-18BP blood levels. The authors concluded that IL-18F blood levels are enhanced in patients with PaCa, despite elevated IL-18BP levels, and the elevated IL-18F blood levels are associated with poor survival in patients with PaCa and suggested that additional studies are needed to determine the proper application of IL-18 in cancer therapy.

Novick et al. (10) investigated patients with systemic lupus erythematosus (SLE) and measured IL-18, IL-18BP and IL-18F blood levels from 48 patients with SLE (total of 195 samples) versus 100 healthy volunteers. They found that IL-18, IL-18BP, and IL-18F blood levels in patients with SLE were significantly higher than their levels in healthy controls (IL-18/IL-18BP/IL-18F, 5×/6×/3× (fold), respectively). The authors suggested that SLE is an autoimmune disease characterized by the production of proinflammatory CYTs and high IL-18 and IL-18BP blood levels suggest their possible role in the pathogenesis and course of the SLE disease.

Girard et al. (11) measured IL-18F, IL-18, IL-18BP and other CYT blood levels in 37 patients with adult-onset Still’s disease (AOSD). The IL-18F blood levels were significantly higher in patients with AOSD (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; p<0.01) and the IL-18F blood levels correlated with AOSD activity. The authors concluded that the IL-18F blood levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.

Girard-Guyonvarc’h et al. (12) and Weiss et al. (13) investigated the role of IL-18, Il-18BP, and IL-18F in macrophage activation syndrome (MAS), which is a life-threatening condition characterized by acute inflammation and a CYT storm. Using two different mouse models of IL-18 overactivity; mice overexpressing IL-18 and mice deficient in IL-18BP, these two studies reported that increased IL-18F blood levels are involved in the development of MAS and that enhanced total IL-18 and IL-18F blood levels increase the risk of developing MAS. In addition, both authors (12, 13) highlighted the importance of IL-18F blood levels in patients with MAS.

Fauteux-Daniel et al. (14) reviewed the role of IL-18, Il-18BP, and IL-18F in the context of systemic inflammatory diseases and pointed out, that there is a need to accurately measure the total IL-18, IL-18F, and IL-18BP blood levels as biomarkers of disease activity and as stratification for potential anti-IL-18 therapy. They also presented the latest techniques to measure total IL-18, IL-18F, and IL-18BP in different samples.

Marino et al. (15) assessed the immune response to the SARS-CoV-2 infection versus patient outcome analyzing IL-18, IL-18BP, INF-γ blood levels in patients with SARS-CoV-2 infection. The enrolled patients were divided in two severity groups according to arterial oxygen and fraction of inspired oxygen and according to the lung involvement at computed tomography. In the group of patients with a more severe disease, a significant increase of the IL-18, INF-γ, and IL-18BP blood levels was observed.

Nasser et al. (16) showed that SARS-CoV-2 infection shares clinical similarities with MAS, which can be driven by elevated IL-18F due to failure of negative-feedback release of IL-18BP. We, therefore, designed a prospective, longitudinal cohort study to examine IL-18 negative-feedback control in relation to SARS-CoV-2 infection. Blood samples from 206 patients with SARS-CoV-2 infection were analyzed for IL-18, IL-18BP, and IL18F. Enhanced IL-18F levels from symptom day 15 onwards were associated with COVID-19 severity and mortality.

Taken together, the aim was to investigate IL-18F levels in 56 patients subjected to MLa and to report their link with seven CYTs, hs-CRP, Casp1, 4-HNE and two pain scores. The results showed that IL-18F levels correlated to IL-18/Il-18BP levels, to lipid peroxidation (LP) biomarker 4-HNE levels and to BPI pain score. The present data indicate that some of the currently available biomarkers seem to have the potential to enhance the diagnostic accuracy of pain testing. Since we did not observe the up-regulation of IL-1β and Casp1 together with IL-18F, it can be assumed that nucleotide-binding domain and leucine-rich repeat pyrin containing protein 3 (NLRP3) inflammasome protein complex is not activated during MLa and pain. In certain stress conditions, IL-18 rather than IL-1β is more sensitive to oxidative stress stimuli and LP without inflammasome activation (26). Of the eight CYTs tested in the present study, the correlation between IL-18F and BPI pain score is an interesting and novel observation. Given that the pain scoring and the potency of analgesics differs among patients (27), it has been proposed that the APR process would impact pain scales (28-30). This assumption is based on the idea that APR may activate opioid receptors; however, this study suggests that CYTs could be utilized to evaluate analgesic efficacy or serve as treatment biomarkers (31, 32).

Conclusion

The studies to date investigating the impact of IL-18/IL-18BP ratio on APR and pain risk have not considered IL-18F blood levels. Until now, the absence of suitable methods has hindered progress in calculating IL-18F blood levels. In the present study, we detected the variation in IL-18/IL-18BP blood levels, enabling us to calculate the IL-18F blood levels at PRE and POP and to report the levels of IL-18F and seven CYTs, hs-CRP, Casp1, and 4-HNE in patients subjected to MLa compared to two pain scales. The present study showed that IL-18F levels decreased significantly after operation and correlated to IL-18, IL-18BP, and 4-HNE blood levels and BPI scores and suggests the applicability of these biomarkers to better understand POP pain.

Acknowledgements

The study was funded by the North Savo Regional Fund (Pohjois-Savon Maakuntarahasto).

Footnotes

  • Authors’ Contributions

    All Authors contributed to the collection and analysis of data, drafting and revising the manuscript, and read and approved the final article.

  • Conflicts of Interest

    The Authors have no conflicts of interest or financial ties to disclose in relation to this study.

  • Received December 15, 2024.
  • Revision received December 31, 2024.
  • Accepted January 3, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Lee JK,
    2. Kim SH,
    3. Lewis EC,
    4. Azam T,
    5. Reznikov LL,
    6. Dinarello CA
    : Differences in signaling pathways by IL-1beta and IL-18. Proc Natl Acad Sci USA 101(23): 8815-8820, 2004. DOI: 10.1073/pnas.0402800101
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Garlanda C,
    2. Mantovani A
    : Ligands and receptors of the interleukin-1 family in immunity and disease. Front Immunol 4: 396, 2013. DOI: 10.3389/fimmu.2013.00396
    OpenUrlCrossRefPubMed
  3. ↵
    1. Garlanda C,
    2. Dinarello CA,
    3. Mantovani A
    : The interleukin-1 family: back to the future. Immunity 39(6): 1003-1018, 2013. DOI: 10.1016/j.immuni.2013.11.010
    OpenUrlCrossRefPubMed
  4. ↵
    1. Dinarello CA
    : Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83(2): 447S-455S, 2006. DOI: 10.1093/ajcn/83.2.447S
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Dinarello CA,
    2. Novick D,
    3. Kim S,
    4. Kaplanski G
    : Interleukin-18 and IL-18 binding protein. Front Immunol 4: 289, 2013. DOI: 10.3389/fimmu.2013.00289
    OpenUrlCrossRefPubMed
  6. ↵
    1. Yamanishi K,
    2. Hata M,
    3. Gamachi N,
    4. Watanabe Y,
    5. Yamanishi C,
    6. Okamura H,
    7. Matsunaga H
    : Molecular mechanisms of IL18 in disease. Int J Mol Sci 24(24): 17170, 2023. DOI: 10.3390/ijms242417170
    OpenUrlCrossRefPubMed
  7. ↵
    1. Chalikias GK,
    2. Tziakas DN,
    3. Kaski JC,
    4. Hatzinikolaou EI,
    5. Stakos DA,
    6. Tentes IK,
    7. Kortsaris A,
    8. Hatseras DI
    : Interleukin-18: Interleukin-10 ratio and in-hospital adverse events in patients with acute coronary syndrome. Atherosclerosis 182(1): 135-143, 2005. DOI: 10.1016/j.atherosclerosis.2005.02.002
    OpenUrlCrossRefPubMed
  8. ↵
    1. Thompson SR,
    2. Novick D,
    3. Stock CJ,
    4. Sanders J,
    5. Brull D,
    6. Cooper J,
    7. Woo P,
    8. Miller G,
    9. Rubinstein M,
    10. Humphries SE
    : Free interleukin (IL)-18 levels, and the impact of IL18 and IL18BP genetic variation, in CHD patients and healthy men. Arterioscler Thromb Vasc Biol 27(12): 2743-2749, 2007. DOI: 10.1161/ATVBAHA.107.149245
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Carbone A,
    2. Vizio B,
    3. Novarino A,
    4. Mauri FA,
    5. Geuna M,
    6. Robino C,
    7. Brondino G,
    8. Prati A,
    9. Giacobino A,
    10. Campra D,
    11. Chiarle R,
    12. Fronda GR,
    13. Ciuffreda L,
    14. Bellone G
    : IL-18 paradox in pancreatic carcinoma: elevated serum levels of free IL-18 are correlated with poor survival. J Immunother 32(9): 920-931, 2009. DOI: 10.1097/CJI.0b013e3181b29168
    OpenUrlCrossRef
  10. ↵
    1. Novick D,
    2. Elbirt D,
    3. Miller G,
    4. Dinarello CA,
    5. Rubinstein M,
    6. Sthoeger ZM
    : High circulating levels of free interleukin-18 in patients with active SLE in the presence of elevated levels of interleukin-18 binding protein. J Autoimmun 34(2): 121-126, 2010. DOI: 10.1016/j.jaut.2009.08.002
    OpenUrlCrossRefPubMed
  11. ↵
    1. Girard C,
    2. Rech J,
    3. Brown M,
    4. Allali D,
    5. Roux-Lombard P,
    6. Spertini F,
    7. Schiffrin EJ,
    8. Schett G,
    9. Manger B,
    10. Bas S,
    11. Del Val G,
    12. Gabay C
    : Elevated serum levels of free interleukin-18 in adult-onset Still’s disease. Rheumatology 55(12): 2237-2247, 2016. DOI: 10.1093/rheumatology/kew300
    OpenUrlCrossRefPubMed
  12. ↵
    1. Girard-Guyonvarc’h C,
    2. Palomo J,
    3. Martin P,
    4. Rodriguez E,
    5. Troccaz S,
    6. Palmer G,
    7. Gabay C
    : Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood 131(13): 1430-1441, 2018. DOI: 10.1182/blood-2017-06-789552
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Weiss ES,
    2. Girard-Guyonvarc’h C,
    3. Holzinger D,
    4. de Jesus AA,
    5. Tariq Z,
    6. Picarsic J,
    7. Schiffrin EJ,
    8. Foell D,
    9. Grom AA,
    10. Ammann S,
    11. Ehl S,
    12. Hoshino T,
    13. Goldbach-Mansky R,
    14. Gabay C,
    15. Canna SW
    : Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood 131(13): 1442-1455, 2018. DOI: 10.1182/blood-2017-12-820852
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Fauteux-Daniel S,
    2. Girard-Guyonvarc’h C,
    3. Caruso A,
    4. Rodriguez E,
    5. Gabay C
    : Detection of free bioactive IL-18 and IL-18BP in inflammatory disorders. Methods Mol Biol 2691: 263-277, 2023. DOI: 10.1007/978-1-0716-3331-1_21
    OpenUrlCrossRefPubMed
  15. ↵
    1. Marino L,
    2. Criniti A,
    3. Guida S,
    4. Bucci T,
    5. Ballesio L,
    6. Suppa M,
    7. Galardo G,
    8. Vacca A,
    9. Santulli M,
    10. Angeloni A,
    11. Lubrano C,
    12. Gandini O
    : Interleukin 18 and IL-18 BP response to Sars-CoV-2 virus infection. Clin Exp Med 23(4): 1243-1250, 2023. DOI: 10.1007/s10238-022-00943-9
    OpenUrlCrossRef
  16. ↵
    1. Nasser SMT,
    2. Rana AA,
    3. Doffinger R,
    4. Kafizas A,
    5. Khan TA,
    6. Nasser S
    : Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients. Intensive Care Med Exp 11(1): 9, 2023. DOI: 10.1186/s40635-022-00488-x
    OpenUrlCrossRefPubMed
    1. Eskelinen M,
    2. Saimanen I,
    3. Selander T,
    4. Holopainen A,
    5. Aspinen S,
    6. Hämäläinen E,
    7. Eskelinen M
    : Interleukin-18 (IL-18) cytokine serum concentrations correlate with pain scores and the number of analgesic doses following surgery. Anticancer Res 42(11): 5521-5526, 2022. DOI: 10.21873/anticanres.16057
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Eskelinen M,
    2. Saimanen I,
    3. Pulkkinen J,
    4. Selander T,
    5. Holopainen A,
    6. Hämäläinen E,
    7. Eskelinen M
    : A possible role of interleukin-18 binding protein in immune regulation of postoperative pain: a prospective randomized clinical trial. Anticancer Res 43(7): 3113-3119, 2023. DOI: 10.21873/anticanres.16483
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Eskelinen M,
    2. Selander T,
    3. Pulkkinen J,
    4. Hämäläinen E,
    5. Eskelinen M
    : Blood interleukin-18 (IL-18) and IL-18 binding protein (IL-18BP) levels following midline laparotomy: a prospective randomized study of patients with benign disease and patients with cancer. Anticancer Res 44(5): 2039-2046, 2024. DOI: 10.21873/anticanres.17007
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Eskelinen M,
    2. Selander T,
    3. Saimanen I,
    4. Pulkkinen J,
    5. Hämäläinen E,
    6. Eskelinen M
    : Brief pain inventory (BPI) pain survey versus cysteine protease caspase-1 (Casp1) blood levels following midline laparotomy: a prospective randomized study of patients with benign disease and patients with cancer. Anticancer Res 44(8): 3463-3471, 2024. DOI: 10.21873/anticanres.17166
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Karema-Jokinen V,
    2. Koskela A,
    3. Hytti M,
    4. Hongisto H,
    5. Viheriälä T,
    6. Liukkonen M,
    7. Torsti T,
    8. Skottman H,
    9. Kauppinen A,
    10. Nymark S,
    11. Kaarniranta K
    : Crosstalk of protein clearance, inflammasome, and Ca(2+) channels in retinal pigment epithelium derived from age-related macular degeneration patients. J Biol Chem 299(6): 104770, 2023. DOI: 10.1016/j.jbc.2023.104770
    OpenUrlCrossRefPubMed
  22. ↵
    1. Purdy M,
    2. Kokki M,
    3. Anttila M,
    4. Aspinen S,
    5. Juvonen P,
    6. Selander T,
    7. Kokki H,
    8. Pulkki K,
    9. Eskelinen M
    : Does post-surgery placement of rectus sheath block analgesia alter the oxidative stress biomarker 8-OHdG concentrations: a randomised trial of patients with cancer and benign disease. Cancer Genomics Proteomics 13(3): 239-244, 2016.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Purdy M,
    2. Kokki M,
    3. Anttila M,
    4. Aspinen S,
    5. Juvonen P,
    6. Korhonen R,
    7. Selander T,
    8. Kokki H,
    9. Eskelinen M
    : Does the rectus sheath block analgesia reduce the inflammatory response biomarker IL-1ra, IL-6, IL-8, IL-10 and IL-1β concentrations following surgery? A randomised clinical trial of patients with cancer and benign disease. Anticancer Res 36(6): 3005-3011, 2016.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Eskelinen M,
    2. Saimanen I,
    3. Koskela R,
    4. Holopainen A,
    5. Selander T,
    6. Eskelinen M
    : Plasma concentration of the lipid peroxidation (LP) biomarker 4-hydroxynonenal (4-HNE) in benign and cancer patients. In Vivo 36(2): 773-779, 2022. DOI: 10.21873/invivo.12764
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Kuosmanen V,
    2. Ruottinen M,
    3. Rahkola D,
    4. Saimanen I,
    5. Kaaronen V,
    6. Selander T,
    7. Purdy M,
    8. Kokki H,
    9. Kokki M,
    10. Eskelinen M
    : Brief pain inventory (BPI) health survey after midline laparotomy with the rectus sheath block (RSB) analgesia: a randomised trial of patients with cancer and benign disease. Anticancer Res 39(12): 6751-6757, 2019. DOI: 10.21873/anticanres.13890
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Korhonen E,
    2. Piippo N,
    3. Hytti M,
    4. Hyttinen JMT,
    5. Kaarniranta K,
    6. Kauppinen A
    : Only IL-1β release is inflammasome-dependent upon ultraviolet B irradiation although IL-18 is also secreted. FASEB J 34(5): 6437-6448, 2020. DOI: 10.1096/fj.201902355RR
    OpenUrlCrossRefPubMed
  27. ↵
    1. Mystakidou K,
    2. Liossi C,
    3. Fragiadakis K,
    4. Georgaki S,
    5. Papadimitriou J
    : What do Greek physicians know about managing cancer pain? J Cancer Educ 13(1): 39-42, 1998. DOI: 10.1080/08858199809528509
    OpenUrlCrossRefPubMed
  28. ↵
    1. Makimura C,
    2. Arao T,
    3. Matsuoka H,
    4. Takeda M,
    5. Kiyota H,
    6. Tsurutani J,
    7. Fujita Y,
    8. Matsumoto K,
    9. Kimura H,
    10. Otsuka M,
    11. Koyama A,
    12. Imamura CK,
    13. Yamanaka T,
    14. Tanaka K,
    15. Nishio K,
    16. Nakagawa K
    : Prospective study evaluating the plasma concentrations of twenty-six cytokines and response to morphine treatment in cancer patients. Anticancer Res 31(12): 4561-4568, 2011.
    OpenUrlAbstract/FREE Full Text
    1. Manchikanti L,
    2. Kaye AM,
    3. Knezevic NN,
    4. Giordano J,
    5. Applewhite MK,
    6. Bautista A,
    7. Soin A,
    8. Blank SK,
    9. Sanapati MR,
    10. Karri J,
    11. Christo PJ,
    12. Abd-Elsayed A,
    13. Kaye AD,
    14. Calodney A,
    15. Navani A,
    16. Gharibo CG,
    17. Harned M,
    18. Gupta M,
    19. Broachwala M,
    20. Sehgal N,
    21. Kaufman A,
    22. Wargo B,
    23. Solanki DR,
    24. Hsu ES,
    25. Limerick G,
    26. Dennis A,
    27. Swicegood JR,
    28. Slavin K,
    29. Snook L,
    30. Pasupuleti R,
    31. Kosanovic R,
    32. Justiz R,
    33. Barkin R,
    34. Atluri S,
    35. Shah S,
    36. Pampati V,
    37. Helm Ii S,
    38. Grami V,
    39. Myckowiak V,
    40. Galan V,
    41. Singh V,
    42. Manocha V,
    43. Hirsch JA
    : Comprehensive, evidence-based, consensus guidelines for prescription of opioids for chronic non-cancer pain from the American Society of Interventional Pain Physicians (ASIPP). Pain Physician 26(7S): S7-S126, 2023.
    OpenUrlPubMed
  30. ↵
    1. Párraga JP,
    2. Castellanos A
    : A manifesto in defense of pain complexity: a critical review of essential insights in pain neuroscience. J Clin Med 12(22): 7080, 2023. DOI: 10.3390/jcm12227080
    OpenUrlCrossRefPubMed
  31. ↵
    1. Luongo M,
    2. Brigida AL,
    3. Mascolo L,
    4. Gaudino G
    : Possible therapeutic effects of ozone mixture on hypoxia in tumor development. Anticancer Res 37(2): 425-436, 2017. DOI: 10.21873/anticanres.11334
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Wakana H,
    2. Kono H,
    3. Fukushima H,
    4. Nakata Y,
    5. Akazawa Y,
    6. Maruyama S,
    7. Hagio K,
    8. Fujii H,
    9. Ichikawa D
    : Effects of medium-chain triglycerides administration in chemically-induced carcinogenesis in mice. Anticancer Res 39(12): 6653-6660, 2019. DOI: 10.21873/anticanres.13880
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Free Interleukin 18 (IL-18F) Blood Levels Following Midline Laparotomy: A Prospective Randomized Study of Patients With Benign Disease and Patients With Cancer
MAARET ESKELINEN, TUOMAS SELANDER, JUKKA PULKKINEN, KAI KAARNIRANTA, ESA HÄMÄLÄINEN, MATTI ESKELINEN
Anticancer Research Feb 2025, 45 (2) 667-675; DOI: 10.21873/anticanres.17454
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords