**1. Introduction**

Pancreatic ductal adenocarcinoma (PDAC) is known for notoriously difficult early diagnostics, almost complete lack of well-defined risk groups for targeted surveillance and poor response to treatment in advanced stages. Thus, PDAC remains among the most challenging cancers for medical professionals today. By incidence, pancreatic cancer was estimated to be the 12th most frequent malignant tumour worldwide in the year 2012. However, it ranked seventh in the global estimates of oncological mortality for the same year. The dismal prognosis is reflected in the high mortality-to-incidence ratio reaching 0.98 [1]. Pancreatic cancer encompasses 2.4% of global cancer incidence and 4.0% of cancer-attributable death cases in the world. Even more, it was predicted to be the fourth leading cause of oncological mortality in Europe, comprising 6% of cancer-induced death events in 2017 [2]. Considering the growing incidence, that might be attributable to the epidemic of obesity and metabolic syndrome, and low 5-year survival rate (6%), USA research teams have generated prognosis that pancreatic cancer might become the second most common cause of oncological mortality by the year 2030 [3].

PDAC is responsible for the bulk of pancreatic cancer burden as it is the most common and aggressive pancreatic tumour [4]. The overall survival and long-term survival rates of patients diagnosed with PDAC generally have not improved in last 30 years, despite multiple innovations in the surgery, including resection of multiple organs; anaesthesia; patient referral for surgery in accordance to surgeon's experience and the excellence of medical team/centre; molecular studies and trends towards personalised treatment as well as appearance of new drugs [3–5].

Currently, pTNM is the mainstay for pancreatic cancer staging [4]. Molecular portrait is important to select targets for personalised treatment. It can have a prognostic role as well. However, the current situation forces to look for additional prognostic factors in PDAC, aiming to stratify patient groups by the predicted treatment response or to adjust the necessary treatment intensity in order to improve the survival or life quality.

accordance to cellular maturity and life cycle: retention of immature myeloid cells in the bone marrow, release of mature cells upon necessity and return of ageing neutrophils that must be destroyed. Consequently, the neutrophil counts in blood of cancer patients increase, and there

**Class Summary activity Features and mechanisms References**

ROS immunostimulatory:

• low activity of arginase • lead to activation of T cells

• high levels of Fas, TNF alpha, CCL3, ICAM1;

Systemic Inflammatory Response in Pancreatic Ductal Adenocarcinoma

Imunosuppressive: high activity of arginase Angiogenic: vascular endothelial growth factor

Facilitate invasion: matrix metalloproteinases (MMP)

Produce pro-inflammatory cytokines TNF alpha, IL-1,

Enhance antigen presentation to T lymphocytes

Immunosuppressive: secret IL-10, arginase,

transforming growth factor beta Down-regulate MHC class II Facilitate angiogenesis Promote cancer cell migration

[9]

5

http://dx.doi.org/10.5772/intechopen.78954

[3, 9]

[3] [10]

[3] [10]

N1 neutrophils Anti-tumour Cytotoxic, capable to kill cancer cells: high levels of

(VEGF)

8, MMP9

IL-6, IL-12, IL-23 Express MHC Produce NO synthase

N2 neutrophils Pro-tumour Lack significant cytotoxic activity

M1 macrophages Pro-inflammatory Restrict cancer growth

M2 macrophages Anti-inflammatory Promote cancer growth

In tumour microenvironment, neutrophils can differentiate towards either anti-cancerous N1 or pro-cancerous N2 phenotype (**Table 1**). These subtypes are considered to represent the end points of the activity spectrum, but any neutrophil can exhibit combined traits of both subtypes. Transforming growth factor beta is known as a potent mediator of N2 differentia-

Neutrophils are capable to facilitate the metastatic spread of PDAC. Clusters formed by neutrophils and circulating cells of pancreatic ductal adenocarcinoma have been observed in peritumoural blood vessels. Further, significant relationship was found between neutrophilcharacterising blood indices (neutrophil to lymphocyte ratio) and distant metastasis after curative surgery [11]. These clinical observations are explained by a complex network of pathogenetic events. Neutrophils can promote tumour cell proliferation and invasion (see **Figure 1**), as well as enhance angiogenesis and increase vascular permeability. Neutrophils also represent the main cell population involved in the formation of pre-metastatic niche

can be a shift to immature cell release.

**Table 1.** The subtypes of neutrophils and macrophages.

tion [9].

Recently, systemic inflammatory response (SIR) has been highlighted in different cancers, including PDAC [6–8]. The network of SIR involves cancer microenvironment, bone marrow and metastatic sites, manifesting as the changes of blood cell counts and ratios as well as blood levels of acute phase proteins. SIR encompasses complex interactions between at least three players: the tumour, the innate and adaptive immunity of the host and the distant tissues.

In SIR, the altered functions of bone marrow lead to switches in production and release of inflammatory cells, including neutrophils. Consequently, blood counts of neutrophils increase and immature myeloid derived suppressor cells (MDSC) appear in the peripheral blood.

Neutrophils develop in bone marrow, and 90% of the mature cells remain there until activating stimulus ensures rapid release in appropriate situations. In cancer-induced SIR, neutrophils are ejected from bone marrow in response to colony-stimulating factors that are produced by the malignant cells. In addition, neutrophil response is incited by tissue damage caused by cancer invasion and/ or by tumour necrosis due to hypoxia and insufficient blood supply in the core of growing mass. The colony-stimulating factors influence also the CXCR2/CXCR4 chemokine axis that is responsible for the circulation of neutrophils in


**Table 1.** The subtypes of neutrophils and macrophages.

**1. Introduction**

4 Advances in Pancreatic Cancer

year 2030 [3].

drugs [3–5].

Pancreatic ductal adenocarcinoma (PDAC) is known for notoriously difficult early diagnostics, almost complete lack of well-defined risk groups for targeted surveillance and poor response to treatment in advanced stages. Thus, PDAC remains among the most challenging cancers for medical professionals today. By incidence, pancreatic cancer was estimated to be the 12th most frequent malignant tumour worldwide in the year 2012. However, it ranked seventh in the global estimates of oncological mortality for the same year. The dismal prognosis is reflected in the high mortality-to-incidence ratio reaching 0.98 [1]. Pancreatic cancer encompasses 2.4% of global cancer incidence and 4.0% of cancer-attributable death cases in the world. Even more, it was predicted to be the fourth leading cause of oncological mortality in Europe, comprising 6% of cancer-induced death events in 2017 [2]. Considering the growing incidence, that might be attributable to the epidemic of obesity and metabolic syndrome, and low 5-year survival rate (6%), USA research teams have generated prognosis that pancreatic cancer might become the second most common cause of oncological mortality by the

PDAC is responsible for the bulk of pancreatic cancer burden as it is the most common and aggressive pancreatic tumour [4]. The overall survival and long-term survival rates of patients diagnosed with PDAC generally have not improved in last 30 years, despite multiple innovations in the surgery, including resection of multiple organs; anaesthesia; patient referral for surgery in accordance to surgeon's experience and the excellence of medical team/centre; molecular studies and trends towards personalised treatment as well as appearance of new

Currently, pTNM is the mainstay for pancreatic cancer staging [4]. Molecular portrait is important to select targets for personalised treatment. It can have a prognostic role as well. However, the current situation forces to look for additional prognostic factors in PDAC, aiming to stratify patient groups by the predicted treatment response or to adjust the necessary

Recently, systemic inflammatory response (SIR) has been highlighted in different cancers, including PDAC [6–8]. The network of SIR involves cancer microenvironment, bone marrow and metastatic sites, manifesting as the changes of blood cell counts and ratios as well as blood levels of acute phase proteins. SIR encompasses complex interactions between at least three players: the tumour, the innate and adaptive immunity of the host and the distant tissues.

In SIR, the altered functions of bone marrow lead to switches in production and release of inflammatory cells, including neutrophils. Consequently, blood counts of neutrophils increase and immature myeloid derived suppressor cells (MDSC) appear in the peripheral blood.

Neutrophils develop in bone marrow, and 90% of the mature cells remain there until activating stimulus ensures rapid release in appropriate situations. In cancer-induced SIR, neutrophils are ejected from bone marrow in response to colony-stimulating factors that are produced by the malignant cells. In addition, neutrophil response is incited by tissue damage caused by cancer invasion and/ or by tumour necrosis due to hypoxia and insufficient blood supply in the core of growing mass. The colony-stimulating factors influence also the CXCR2/CXCR4 chemokine axis that is responsible for the circulation of neutrophils in

treatment intensity in order to improve the survival or life quality.

accordance to cellular maturity and life cycle: retention of immature myeloid cells in the bone marrow, release of mature cells upon necessity and return of ageing neutrophils that must be destroyed. Consequently, the neutrophil counts in blood of cancer patients increase, and there can be a shift to immature cell release.

In tumour microenvironment, neutrophils can differentiate towards either anti-cancerous N1 or pro-cancerous N2 phenotype (**Table 1**). These subtypes are considered to represent the end points of the activity spectrum, but any neutrophil can exhibit combined traits of both subtypes. Transforming growth factor beta is known as a potent mediator of N2 differentiation [9].

Neutrophils are capable to facilitate the metastatic spread of PDAC. Clusters formed by neutrophils and circulating cells of pancreatic ductal adenocarcinoma have been observed in peritumoural blood vessels. Further, significant relationship was found between neutrophilcharacterising blood indices (neutrophil to lymphocyte ratio) and distant metastasis after curative surgery [11]. These clinical observations are explained by a complex network of pathogenetic events. Neutrophils can promote tumour cell proliferation and invasion (see **Figure 1**), as well as enhance angiogenesis and increase vascular permeability. Neutrophils also represent the main cell population involved in the formation of pre-metastatic niche before malignant cells arrive to the site of metastasis. In the pre-metastatic niches, neutrophils and immature bone marrow-derived cells gather in clusters that ensure tumour cell homing. When circulating tumour cells reach the 'prepared' metastatic site, neutrophils anchor cancer cells to the endothelium, facilitating trans-endothelial migration and invasion. Indeed, malignant cells entrapped in distant organs produce cytokines to attract neutrophils. The classic inflammation-related adhesion molecules, including integrins, can promote cancer cell adhesion [9]. Thus, interleukin-induced expression of ICAM1 has been shown to support the extravasation of malignant cells and pathogenesis of the PDAC metastasis [12]. Leukotrienes, secreted by neutrophils, further promote tumour cell proliferation and growth of the metastasis [9]. To enhance carcinogenesis, neutrophils act in concert with macrophages, similarly to the parallel effects of MDSCs and M2 macrophages. For instance, bone marrow-derived macrophages are involved in the generation of premetastatic niches by pancreatic cancer exosomes [13].

Neutrophils along with macrophages and other innate immunity cells are considered to have predominantly pro-tumourous activity, contrasting with adaptive immunity (lymphocytes) having protective role. However, this assumption is not straightforward—N1 neutrophils exhibit contra-cancer activity. Type I interferons can convert neutrophils into anti-tumourous fighters with rich armoury: enhanced production of ROS, suppressed ability to form premetastatic niches, upregulated ROS-mediated killing of NET-trapped cancer cells, active direct cytotoxicity (via ROS or antibody-dependent cell-mediated cytotoxicity) and improved

Systemic Inflammatory Response in Pancreatic Ductal Adenocarcinoma

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7

MDSCs represent heterogeneous population of immature cells (namely, the precursors of granulocytes, macrophages, monocytes and dendritic cells) sharing immunosuppressive function and myeloid origin. These cells express wide spectrum of enzymes, inflammatory mediators as well as reactive oxygen species and/or reactive nitrogen intermediates [3]. MDSCs travel via blood from their site of origin in bone marrow to the tumour and to peripheral tissues. In the cancer microenvironment, MDSCs along with M2 macrophages (see **Table 1**) exert immunosuppressive effect [16]. Within the complex immunosuppressive network of events in tumours stroma, MDSCs suppress the activity of CD8-positive T lymphocytes; induce T-cell apoptosis by ROS and nitric oxide derivatives; promote T-cell anergy via regulatory T lymphocytes; inhibit T cell migration via nitration of chemokines and T-cell receptors; block interferon (IFN) gamma pathway and cleave arginine and cysteine via upregulated arginase. The IFN gamma, arginine and cysteine are essential for T lymphocyte activity. In addition to the anti-T cell activities, MDSCs block the M1 phenotype of tumour-infiltrating macrophages. Production of pro-inflammatory interleukin (IL) 6 by MSDCs promote JAK/STAT mediated pathways stimulating cancer cell proliferation, survival and evasion from antigen presentation to dendritic cells [3]. In distant tissues, immature myeloid cells participate in the generation of pre-metastatic niches [14, 17].

The activities of neutrophils and MDSC in tumour stroma are carried out in cooperation with tumour-infiltrating macrophages. Macrophages are recruited by cancer-produced signal molecules, including cytokines and growth factors, as well as by tumour necrosis. In cancer microenvironment, macrophages acquire M2 differentiation and can enhance tumour progression, angiogenesis and metastatic spread [10]. M2 macrophages along with MDSC are immune suppressors in the cancer stroma [16]. In distant tissues, macrophages assist in the creation of premetastatic niches. As noted, this mechanism has been demonstrated in PDAC: bone marrow-derived macrophages are involved in the generation of premetastatic niches by

In turn, lymphocytes mostly play a defensive role against cancer in the whole body and in

The pathogenetic association between PDAC and activated blood clotting is acknowledged for centuries, reflected by the historic descriptions of migratory thrombophlebitis, also known as Trousseau syndrome. The related clinical events include thromboembolism and nonbacterial thrombotic endocarditis in cancer patients, occasionally manifesting as the first sign of malignant disease [18]. In peripheral blood, platelet counts increase in response to local cancer invasion causing endothelial damage. The platelet response is also generated by the pro-inflammatory cytokines (IL-1, IL-3 and IL-6) that are produced by the cancer and promote megakaryocyte

development [8]. Thrombocytosis has been observed in 15.2% of PDAC patients [19].

capacity to stimulate adaptive immunity [9].

pancreatic cancer exosomes [13].

tumour microenvironment [10].

Within the framework of SIR, neutrophils derive unique structures—neutrophil extracellular traps (NETs). NETs represent a mesh of chromatin and nuclear proteins [9]. These structures possibly have evolutionary developed as a mechanism of antimicrobial response. In cancer patient, NETs can wrap a circulating tumour cell, resulting in either reactive oxygen species (ROS)-mediated destruction or facilitated adhesion in a pre-metastatic niche. NETosis evolves in different stressful conditions, including pre-eclampsia, major surgery or surgical infection. Consequently, surgery is not only a mechanical tool to withdraw the tumour from the body, but it can also become a major immunologic switch. Prolonged or complicated surgical intervention might threaten patient's life directly but also through SIR-associated pathways. Indeed, surgical stress or postsurgical infection is shown to facilitate metastatic spread, and NETosis is demonstrated in these conditions [9]. SIR-based molecular events highlight the association between infection or surgery-induced inflammation [14, 15] and recurrence or metastatic spread of the cancer.

**Figure 1.** The main pathogenetic events in metastatic dissemination of cancer. Abbreviations: Neu, neutrophils; Mf, macrophages; Plt, platelets; MDSC, myeloid derived suppressor cells; NETs, neutrophil extracellular traps.

Neutrophils along with macrophages and other innate immunity cells are considered to have predominantly pro-tumourous activity, contrasting with adaptive immunity (lymphocytes) having protective role. However, this assumption is not straightforward—N1 neutrophils exhibit contra-cancer activity. Type I interferons can convert neutrophils into anti-tumourous fighters with rich armoury: enhanced production of ROS, suppressed ability to form premetastatic niches, upregulated ROS-mediated killing of NET-trapped cancer cells, active direct cytotoxicity (via ROS or antibody-dependent cell-mediated cytotoxicity) and improved capacity to stimulate adaptive immunity [9].

before malignant cells arrive to the site of metastasis. In the pre-metastatic niches, neutrophils and immature bone marrow-derived cells gather in clusters that ensure tumour cell homing. When circulating tumour cells reach the 'prepared' metastatic site, neutrophils anchor cancer cells to the endothelium, facilitating trans-endothelial migration and invasion. Indeed, malignant cells entrapped in distant organs produce cytokines to attract neutrophils. The classic inflammation-related adhesion molecules, including integrins, can promote cancer cell adhesion [9]. Thus, interleukin-induced expression of ICAM1 has been shown to support the extravasation of malignant cells and pathogenesis of the PDAC metastasis [12]. Leukotrienes, secreted by neutrophils, further promote tumour cell proliferation and growth of the metastasis [9]. To enhance carcinogenesis, neutrophils act in concert with macrophages, similarly to the parallel effects of MDSCs and M2 macrophages. For instance, bone marrow-derived macrophages are involved in the generation of premetastatic niches by pancreatic cancer exo-

Within the framework of SIR, neutrophils derive unique structures—neutrophil extracellular traps (NETs). NETs represent a mesh of chromatin and nuclear proteins [9]. These structures possibly have evolutionary developed as a mechanism of antimicrobial response. In cancer patient, NETs can wrap a circulating tumour cell, resulting in either reactive oxygen species (ROS)-mediated destruction or facilitated adhesion in a pre-metastatic niche. NETosis evolves in different stressful conditions, including pre-eclampsia, major surgery or surgical infection. Consequently, surgery is not only a mechanical tool to withdraw the tumour from the body, but it can also become a major immunologic switch. Prolonged or complicated surgical intervention might threaten patient's life directly but also through SIR-associated pathways. Indeed, surgical stress or postsurgical infection is shown to facilitate metastatic spread, and NETosis is demonstrated in these conditions [9]. SIR-based molecular events highlight the association between infection or surgery-induced inflammation [14, 15] and recurrence or

> Detachment of individual cells and invasion in blood vessels or lymphatics

Neu, Mf, Plt Neu, Mf, Plt Neu, Plt

at the secondary site

Growth of the metastasis to gross size Neu, Mf

**Figure 1.** The main pathogenetic events in metastatic dissemination of cancer. Abbreviations: Neu, neutrophils; Mf,

macrophages; Plt, platelets; MDSC, myeloid derived suppressor cells; NETs, neutrophil extracellular traps.

Pre -metastatic niches Adhesion and extravasation

Migration to the secondary site

Escape of anoikis in blood/ lymph

Neu Neu, Plt

somes [13].

6 Advances in Pancreatic Cancer

metastatic spread of the cancer.

Invasive growth of cancer

Neu, Mf, exosomes, MDSC, NETs, Plt

MDSCs represent heterogeneous population of immature cells (namely, the precursors of granulocytes, macrophages, monocytes and dendritic cells) sharing immunosuppressive function and myeloid origin. These cells express wide spectrum of enzymes, inflammatory mediators as well as reactive oxygen species and/or reactive nitrogen intermediates [3]. MDSCs travel via blood from their site of origin in bone marrow to the tumour and to peripheral tissues. In the cancer microenvironment, MDSCs along with M2 macrophages (see **Table 1**) exert immunosuppressive effect [16]. Within the complex immunosuppressive network of events in tumours stroma, MDSCs suppress the activity of CD8-positive T lymphocytes; induce T-cell apoptosis by ROS and nitric oxide derivatives; promote T-cell anergy via regulatory T lymphocytes; inhibit T cell migration via nitration of chemokines and T-cell receptors; block interferon (IFN) gamma pathway and cleave arginine and cysteine via upregulated arginase. The IFN gamma, arginine and cysteine are essential for T lymphocyte activity. In addition to the anti-T cell activities, MDSCs block the M1 phenotype of tumour-infiltrating macrophages. Production of pro-inflammatory interleukin (IL) 6 by MSDCs promote JAK/STAT mediated pathways stimulating cancer cell proliferation, survival and evasion from antigen presentation to dendritic cells [3]. In distant tissues, immature myeloid cells participate in the generation of pre-metastatic niches [14, 17].

The activities of neutrophils and MDSC in tumour stroma are carried out in cooperation with tumour-infiltrating macrophages. Macrophages are recruited by cancer-produced signal molecules, including cytokines and growth factors, as well as by tumour necrosis. In cancer microenvironment, macrophages acquire M2 differentiation and can enhance tumour progression, angiogenesis and metastatic spread [10]. M2 macrophages along with MDSC are immune suppressors in the cancer stroma [16]. In distant tissues, macrophages assist in the creation of premetastatic niches. As noted, this mechanism has been demonstrated in PDAC: bone marrow-derived macrophages are involved in the generation of premetastatic niches by pancreatic cancer exosomes [13].

In turn, lymphocytes mostly play a defensive role against cancer in the whole body and in tumour microenvironment [10].

The pathogenetic association between PDAC and activated blood clotting is acknowledged for centuries, reflected by the historic descriptions of migratory thrombophlebitis, also known as Trousseau syndrome. The related clinical events include thromboembolism and nonbacterial thrombotic endocarditis in cancer patients, occasionally manifesting as the first sign of malignant disease [18]. In peripheral blood, platelet counts increase in response to local cancer invasion causing endothelial damage. The platelet response is also generated by the pro-inflammatory cytokines (IL-1, IL-3 and IL-6) that are produced by the cancer and promote megakaryocyte development [8]. Thrombocytosis has been observed in 15.2% of PDAC patients [19].


Considering high mortality and poor treatment results of pancreatic ductal adenocarcinoma and the need for prognostic and predictive novelties, this chapter scrutinises the assessment of SIR in PDAC, potential practical implementations and restrictions of those parameters.

Systemic Inflammatory Response in Pancreatic Ductal Adenocarcinoma

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9

Neutrophil to lymphocyte ratio is calculated as the ratio between the count of neutrophilic leukocytes and lymphocytes in peripheral blood, using the values detected in a routine full blood count. Hence, the parameter is easily available, especially in carefully examined cancer patients, and economically nondemanding. In fact, sufficient awareness and algorithm for interpretation are the only prerequisites to obtain an additional piece of information from routine blood tests. At present, the association between NLR and different aspects of survival, for example, overall, recurrence free or cancer-specific survival, remains one of the best sub-

The prognostic importance of NLR is shown over the whole course of PDAC and is applicable to wide treatment spectrum—from surgically resectable early cases to advanced or metastatic tumours eligible only for non-surgical treatment. Several research teams have demonstrated independent prognostic value of NLR, confirmed by multivariate analysis. In few studies, the association with survival is confirmed by univariate but not multivariate analysis. Some of the reports are on better scores, for example, Glasgow prognostic score had higher informativity

Although only a minor fraction (around 20%) of pancreatic cancers are amenable to surgery, surgical removal of tumour is highly advisable, if feasible because surgery provides the only definitive cure [5]. Pre-treatment NLR has been evaluated as a prognostic factor for surgically treated PDAC patients, mostly with positive findings. Thus, in a large cohort of 442 patients subjected to pancreatic resection for PDAC, high NLR was associated with significantly lower median survival. The difference was also biologically important: only 12.6 months in those presenting with high NLR (defined in this study by receiver operating characteristics (ROC) curve analysis as ≥5) patients versus 25.7 months in patients having low NLR. Cox proportional hazards analysis confirmed NLR as an independent prognostic factor, associated with hazard ratio (HR) 1.66; 95% confidence interval (CI): 1.12–2.46; p = 0.012 [21]. In a small group of 46 patients subjected to pancreaticoduodenectomy, high NLR (≥2.5) was associated with lower overall survival rate. In addition, it predicted surgical complications worse than Clavien-Dindo grade 3 [22]. Among 381 patients treated by curative resection of PDAC, high NLR (≥2) was significantly and independently associated with overall survival [23]. The prognostic value was especially clear in stage I/II [24]. In 110 surgically treated pancreatic cancer patients, high NLR (≥5) was an independent prognostic factor for worse cancer-specific

Standard preoperative assessment of NLR is recommended in cases of borderline resectable pancreatic cancer by consensus statement by the International Study Group of Pancreatic Surgery [26].

**2. NLR in pancreatic ductal adenocarcinoma**

stantiated aspects in the SIR research in cancer.

in the study performed by Yamada et al. [20].

survival, as confirmed by p < 0.039 [25].

**2.1. NLR and survival**

**Table 2.** Parameters of systemic inflammatory reaction.

Locally, platelets promote angiogenesis, invasion, production of growth factors and adhesion molecules [8]. Platelets facilitate metastatic spread by creating clusters with circulating tumour cells and protecting them from immune surveillance, promoting the development of pre-metastatic niches and tumour cell attachment to distant tissues. Along with the metastatic spread, platelets are suggested to have a major role in epithelial-mesenchymal transition process during which epithelial malignant cells change the phenotype to mesenchymal-like, plastic cells with enhanced capability for invasion into connective tissues, blood and lymphatic vessels as well as metastatic spread [8].

Considering pathogenetic and prognostic role of the interaction between tumour and host inflammatory response, systemic inflammatory response has recently become a hot topic in medical research. Several indices are elaborated to evaluate SIR (**Table 2**). Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and Glasgow prognostic score (GPS) represent the best-known examples.

Although almost all immune and inflammatory cells can have dual effects in cancer, neutrophils mainly act as tumour promoters while lymphocytes represent the protective innate immunity. Thus, NLR represents the balance between pro- and contra-tumourous immune and inflammatory processes of the host. Similarly, activation of blood clotting is associated with burden of invasive tumour, that damages endothelium like 'dozen of sharp knives', and platelets also facilitate the further development and spread of the cancer while lymphocytes exhibit protective action. Hence, PLR is another measure of equilibrium between pro- and contra-tumourous events within SIR. GPS reflects the upregulation of acute phase protein (measured by the prototypic C-reactive protein) and degree of catabolism by hypoalbuminemia. In addition, combined inflammation-based scores have been proposed, derived from combinations of SIR-related factors in order to reach higher prognostic value.

Considering high mortality and poor treatment results of pancreatic ductal adenocarcinoma and the need for prognostic and predictive novelties, this chapter scrutinises the assessment of SIR in PDAC, potential practical implementations and restrictions of those parameters.
