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Cancers
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Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients
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Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 22195

Special Issue Editor

Prof. Dr. Donal J Buggy

E-Mail Website
Guest Editor
1. Department of Anaesthesiology and Perioperative Medicine, Mater University Hospital, School of Medicine, University College Dublin, Ireland
2. EU-COST Action 15204, Euro-Periscope
3. Outcomes Research, Cleveland Clinic, Cleveland, OH, USA
Interests: cancer recurrence; anaesthesia; analgesia; surgery

Special Issue Information

Dear Colelagues,

Surgery is an important component of treatment for the majority of solid organ tumours. Unfortunately, cancer recurrence following the surgery of curative intent is common, and typically results in refractory disease and patient death. Surgery and other perioperative interventions can induce a biological state conducive to the survival and growth of residual cancer cells released from the primary tumour intra-operatively, which may influence the risk of subsequent metastatic disease. Evidence is accumulating that anaesthetic and analgesic agents could affect many of these pathophysiological processes, influencing risk of cancer recurrence in either a beneficial or detrimental way. Much of this evidence is from experimental in vitro and in vivo models, with clinical evidence limited to retrospective observational studies or the post hoc analysis of randomised controlled trials originally designed to evaluate non-cancer outcomes.  

This Special Issue brings together the best current, peer-reviewed experimental, and clinical evidence regarding this crucial multidisciplinary research question. Proving a causal link will require data from prospective, randomised controlled trials with oncologic outcomes as primary end-points, a number of which are due to be reported in the near future. Until then, the research projects described are the necessary intermediate steps in defining the scientific mechanism underpinning this hypothesis.

Prof. Dr. Donal J Buggy
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (6 papers)

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Research

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15 pages, 1870 KiB  
Article
Association between Intraoperative Blood Transfusion, Regional Anesthesia and Outcome after Pediatric Tumor Surgery for Nephroblastoma
by Sarah D. Müller, Christian P. Both, Christoph Sponholz, Maria Theresa Voelker, Holger Christiansen, Felix Niggli, Achim Schmitz, Markus Weiss, Jörg Thomas, Sebastian N. Stehr and Tobias Piegeler
Cancers 2022, 14(22), 5585; https://doi.org/10.3390/cancers14225585 - 14 Nov 2022
Cited by 2 | Viewed by 1545
Abstract
Background: Recent data suggest that anesthesiologic interventions—e.g., the choice of the anesthetic regimen or the administration of blood products—might play a major role in determining outcome after tumor surgery. In contrast to adult patients, only limited data are available regarding the potential association [...] Read more.
Background: Recent data suggest that anesthesiologic interventions—e.g., the choice of the anesthetic regimen or the administration of blood products—might play a major role in determining outcome after tumor surgery. In contrast to adult patients, only limited data are available regarding the potential association of anesthesia and outcome in pediatric cancer patients. Methods: A retrospective multicenter study assessing data from pediatric patients (0–18 years of age) undergoing surgery for nephroblastoma between 2004 and 2018 was conducted at three academic centers in Europe. Overall and recurrence-free survival were the primary outcomes of the study and were evaluated for a potential impact of intraoperative administration of erythrocyte concentrates, the use of regional anesthesia and the choice of the anesthetic regimen. The length of stay on the intensive care unit, the time to hospital discharge after surgery and blood neutrophil-to-lymphocyte ratio were defined as secondary outcomes. Results: In total, data from 65 patients were analyzed. Intraoperative administration of erythrocyte concentrates was associated with a reduction in recurrence-free survival (hazard ratio (HR) 7.59, 95% confidence interval (CI) 1.36–42.2, p = 0.004), whereas overall survival (HR 5.37, 95% CI 0.42–68.4, p = 0.124) was not affected. The use of regional anesthesia and the choice of anesthetic used for maintenance of anesthesia did not demonstrate an effect on the primary outcomes. It was, however, associated with fewer ICU transfers, a shortened time to discharge and a decreased postoperative neutrophil-to-lymphocyte ratio. Conclusions: The current study provides the first evidence for a possible association between blood transfusion as well as anesthesiologic interventions and outcome after pediatric cancer surgery. Full article
(This article belongs to the Special Issue Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients)
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18 pages, 21392 KiB  
Article
Long-Term Deleterious Effects of Short-term Hyperoxia on Cancer Progression—Is Brain-Derived Neurotrophic Factor an Important Mediator? An Experimental Study
by Adrian Tiron, Irina Ristescu, Paula A. Postu, Crina E. Tiron, Florin Zugun-Eloae and Ioana Grigoras
Cancers 2020, 12(3), 688; https://doi.org/10.3390/cancers12030688 - 14 Mar 2020
Cited by 9 | Viewed by 3493
Abstract
Perioperative factors promoting cancer recurrence and metastasis are under scrutiny. While oxygen toxicity is documented in several acute circumstances, its implication in tumor evolution is poorly understood. We investigated hyperoxia long-term effects on cancer progression and some underlying mechanisms using both in vitro [...] Read more.
Perioperative factors promoting cancer recurrence and metastasis are under scrutiny. While oxygen toxicity is documented in several acute circumstances, its implication in tumor evolution is poorly understood. We investigated hyperoxia long-term effects on cancer progression and some underlying mechanisms using both in vitro and in vivo models of triple negative breast cancer (TNBC). We hypothesized that high oxygen exposure, even of short duration, may have long-term effects on cancer growth. Considering that hyperoxic exposure results in reactive oxygen species (ROS) formation, increased oxidative stress and increased Brain-Derived Neurotrophic Factor (BDNF) expression, BDNF may mediate hyperoxia effects offering cancer cells a survival advantage by increased angiogenesis and epithelial mesenchymal transition (EMT). Human breast epithelial MCF10A, human MDA-MB-231 and murine 4T1 TNBC were investigated in 2D in vitro system. Cells were exposed to normoxia or hyperoxia (40%, 60%, 80% O2) for 6 h. We evaluated ROS levels, cell viability and the expression of BDNF, HIF-1α, VEGF-R2, Vimentin and E-Cadherin by immunofluorescence. The in vivo model consisted of 4T1 inoculation in Balb/c mice and tumor resection 2 weeks after and 6 h exposure to normoxia or hyperoxia (40%, 80% O2). We measured lung metastases and the same molecular markers, immediately and 4 weeks after surgery. The in vitro study showed that short-term hyperoxia exposure (80% O2) of TNBC cells increases ROS, increases BDNF expression and that promotes EMT and angiogenesis. The in vivo data indicates that perioperative hyperoxia enhances metastatic disease and this effect could be BDNF mediated. Full article
(This article belongs to the Special Issue Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients)
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14 pages, 2362 KiB  
Article
Mu Opioid Receptor 1 (MOR-1) Expression in Colorectal Cancer and Oncological Long-Term Outcomes: A Five-Year Retrospective Longitudinal Cohort Study
by Oscar Díaz-Cambronero, Guido Mazzinari, Francisco Giner, Amparo Belltall, Lola Ruiz-Boluda, Anabel Marqués-Marí, Luis Sánchez-Guillén, Pilar Eroles, Juan Pablo Cata and María Pilar Argente-Navarro
Cancers 2020, 12(1), 134; https://doi.org/10.3390/cancers12010134 - 5 Jan 2020
Cited by 24 | Viewed by 3536
Abstract
Preclinical evidence has shown increased expression of mu opioid receptor 1 (MOR-1) in colorectal cancer although its association with disease-free and overall survival (DFS and OS) has not been investigated. We hypothesized that MOR-1 was overexpressed in tumor samples compared to normal tissue [...] Read more.
Preclinical evidence has shown increased expression of mu opioid receptor 1 (MOR-1) in colorectal cancer although its association with disease-free and overall survival (DFS and OS) has not been investigated. We hypothesized that MOR-1 was overexpressed in tumor samples compared to normal tissue and this was associated with decreased DFS and OS. We carried out a retrospective study assessing the association of MOR-1 tumor expression with long-term outcomes by immunohistochemistry in normal and tumor samples from 174 colorectal cancer patients. The primary endpoint was five years of DFS. Secondary endpoints were five years of OS, the difference in MOR-1 expression between normal and tumor tissue and the occurrence of postoperative complications. Multivariable Cox regression showed no significant association between MOR-1 expression and DFS (HR 0.791, 95% CI 0.603–1.039, p = 0.092). MOR-1 expression was higher in tumor tissue compared to non-tumor tissue. No associations were found between MOR-1 expression and OS or postoperative complications. These findings suggest that although MOR-1 is over-expressed in colorectal cancer samples there is no association to increased risk of recurrence or mortality. Future studies are warranted to elucidate the role of cancer stage, genetic polymorphism, and quantitative assessment of MOR-1 over-expression on long-term outcomes in colorectal cancer. Full article
(This article belongs to the Special Issue Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients)
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10 pages, 1850 KiB  
Article
Effects of Lidocaine and Src Inhibition on Metastasis in a Murine Model of Breast Cancer Surgery
by Thomas P. Wall, Peter D. Crowley, Aislinn Sherwin, Andrew G. Foley and Donal J. Buggy
Cancers 2019, 11(10), 1414; https://doi.org/10.3390/cancers11101414 - 22 Sep 2019
Cited by 37 | Viewed by 4100
Abstract
Breast cancer recurs in 20% of patients following intended curative resection. In vitro data indicates that amide local anaesthetics, including lidocaine, inhibit cancer cell metastasis by inhibiting the tyrosine kinase enzyme Src. In a murine breast cancer surgery model, systemic lidocaine reduces postoperative [...] Read more.
Breast cancer recurs in 20% of patients following intended curative resection. In vitro data indicates that amide local anaesthetics, including lidocaine, inhibit cancer cell metastasis by inhibiting the tyrosine kinase enzyme Src. In a murine breast cancer surgery model, systemic lidocaine reduces postoperative pulmonary metastases. We investigated whether the additional administration of bosutinib (a known Src inhibitor) influences lidocaine’s observed beneficial effect in this in vivo model. Female BALB/c mice (n = 95) were inoculated with 25,000 4T1 cells into the mammary fad pad and after 7 days the resulting tumours were excised under sevoflurane anaesthesia. Experimental animals were randomized to one of four treatments administered intravenously prior to excision: lidocaine, bosutinib, both lidocaine and bosutinib in combination, or saline. Animals were euthanized 14 days post-surgery and lung and liver metastatic colonies were evaluated. Post-mortem serum was analysed for MMP-2 and MMP-9, pro-metastatic enzymes whose expression is influenced by the Src pathway. Lidocaine reduced lung, but not liver metastatic colonies versus sevoflurane alone (p = 0.041), but bosutinib alone had no metastasis-inhibiting effect. When combined with lidocaine, bosutinib reversed the anti-metastatic effect observed with lidocaine on sevoflurane anaesthesia. Only lidocaine alone reduced MMP-2 versus sevoflurane (p = 0.044). Both bosutinib (p = 0.001) and bosutinib/lidocaine combined (p = 0.001) reduced MMP-9 versus sevoflurane, whereas lidocaine alone did not. In a murine surgical breast cancer model, the anti-metastatic effects of lidocaine under sevoflurane anaesthesia are abolished by the Src inhibitor bosutinib, and lidocaine reduces serum MMP-2. These results suggest that lidocaine may act, at least partly, via an inhibitory effect on MMP-2 expression to reduce pulmonary metastasis, but whether this is due to an effect on Src or via another pathway remains unclear. Full article
(This article belongs to the Special Issue Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients)
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Review

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25 pages, 766 KiB  
Review
Interaction of Opioids with TLR4—Mechanisms and Ramifications
by Mai Mahmoud Gabr, Iqira Saeed, Jared A. Miles, Benjamin P. Ross, Paul Nicholas Shaw, Markus W. Hollmann and Marie-Odile Parat
Cancers 2021, 13(21), 5274; https://doi.org/10.3390/cancers13215274 - 21 Oct 2021
Cited by 27 | Viewed by 4322
Abstract
The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in [...] Read more.
The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent studies of the opioid receptor (OR)-independent actions of opioids have identified that TLR4 can respond to opioids. Opioids are reported to weakly activate TLR4, but to significantly inhibit LPS-induced TLR4 activation. The action of opioids at TLR4 is suggested to be non-stereoselective, this is because OR-inactive (+)-isomers of opioids have been shown to activate or to inhibit TLR4 signalling, although there is some controversy in the literature. While some opioids can bind to the lipopolysaccharide (LPS)-binding cleft of the Myeloid Differentiation factor 2 (MD-2) co-receptor, pharmacological characterisation of the inhibition of opioids on LPS activation of TLR4 indicates a noncompetitive mechanism. In addition to a direct interaction at the receptor, opioids affect NF-κB activation downstream of both TLR4 and opioid receptors and modulate TLR4 expression, leading to a range of in vivo outcomes. Here, we review the literature reporting the activity of opioids at TLR4, its proposed mechanism(s), and the complex functional consequences of this interaction. Full article
(This article belongs to the Special Issue Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients)
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22 pages, 2954 KiB  
Review
Long-Term Outcomes after Use of Perioperative Glucocorticoids in Patients Undergoing Cancer Surgery: A Systematic Review and Meta-Analysis
by Emma Rosenkrantz Hölmich, Rune Petring Hasselager, Michael Tvilling Madsen, Adile Orhan and Ismail Gögenur
Cancers 2020, 12(1), 76; https://doi.org/10.3390/cancers12010076 - 27 Dec 2019
Cited by 9 | Viewed by 4170
Abstract
The surgical stress response can accelerate clinical metastasis formation. Perioperative glucocorticoids might modulate this response and the metastatic process. We aimed to describe associations between perioperative glucocorticoids and long-term outcomes after cancer surgery. We searched four databases for eligible trials and performed meta-analyses [...] Read more.
The surgical stress response can accelerate clinical metastasis formation. Perioperative glucocorticoids might modulate this response and the metastatic process. We aimed to describe associations between perioperative glucocorticoids and long-term outcomes after cancer surgery. We searched four databases for eligible trials and performed meta-analyses on frequency and time-to-event data. We included sixteen studies that evaluated eight different cancer types. No association was found between perioperative glucocorticoids and recurrence in either the frequency meta-analysis, risk ratio (RR) 1.04, 95% confidence interval (CI) (0.87–1.25), or in the time-to-event meta-analysis, hazard ratio (HR) 1.18, 95% CI (0.78–1.79). Increased 1-year overall survival, RR 0.70, 95% (0.51–0.97), and disease-free survival, RR 0.77, 95% CI (0.60–0.97), was found for the glucocorticoid group, but five years after surgery, overall survival was reduced for the glucocorticoid group, RR 1.64, 95% CI (1.00–2.71). An exploratory subgroup analysis revealed decreased overall survival, HR 1.78, 95% CI (1.57–2.03), for patients undergoing colorectal cancer surgery while receiving glucocorticoids. Perioperative glucocorticoids were not associated with recurrence after cancer surgery. We found neither beneficial or deleterious associations between glucocorticoids and overall survival or disease-free survival. The available evidence remains heterogenous; low in quality and amount; and cancer-specific at present. Full article
(This article belongs to the Special Issue Perioperative Interventions and Oncological Outcome in Surgical Cancer Patients)
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