**2. NLR in pancreatic ductal adenocarcinoma**

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 substantiated aspects in the SIR research in cancer.

#### **2.1. NLR and survival**

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 lym-

1 Increased CRP on the background of normal albumin level: CRP > 10 mg/L AND

2 Increased CRP and hypoalbuminemia: CRP > 10 mg/L AND albumin <35 g/L

NLR Ratio between the absolute counts of neutrophils and lymphocytes in the

PLR Ratio between the absolute counts of platelets and lymphocytes in the peripheral

peripheral blood

1 One high-risk finding: CRP ≥ 10 mg/L OR albumin <35 g/L 2 Both high-risk findings: CRP ≥ 10 mg/L AND albumin <35 g/L

blood

0 CRP ≤ 10 mg/L irrespective of albumin level

albumin ≥35 g/L

0 CRP < 10 mg/L AND albumin ≥35 g/L

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)

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.

phatic vessels as well as metastatic spread [8].

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

represent the best-known examples.

**Parameter/score Definition**

Glasgow prognostic score

8 Advances in Pancreatic Cancer

Modified Glasgow prognostic score

Abbreviation: CRP, C-reactive protein.

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

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

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]. In most studies, preoperative NLR has been assessed. However, the patient's immune status after the surgery might be as important. Indeed, postoperative NLR, evaluated 1 month after the surgery, was shown to have a prognostic value for overall and recurrence-free survival. Comparing the patients with NLR ≥ 3 versus NLR < 3.0, the 1-year survival rate was 42.6 versus 81.9% and 3-year survival rate: 7.3 versus 33.9% (p < 0.001). Notably, the differences were confirmed to be statistically significant despite relatively small study group comprising 86 patients [27].

morphological evaluation of the response to preoperative treatment. Poor response was associated with higher pre-treatment NLR [34]. To predict efficacy of chemotherapy, both pre-treatment NLR and its dynamics are considered important. Thus, low baseline NLR and low NLR after first-line chemotherapy were associated with higher efficacy of chemotherapy

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In patients receiving stereotactic radiotherapy for advanced PDAC, high NLR (>5) was associ-

Again, the prognostic role of NLR in advanced pancreatic cancer has not always been confirmed. In 122 patients, undergoing chemotherapy for inoperable pancreatic cancer, both high and low NLR was associated with the same median survival of 10 months. In the same study, the dynamics of NLR still predicted outcomes although the biological difference was tiny: the median overall was 10 versus 11 months; p < 0.001. The dynamics was assessed as the ratio of pre-treatment NLR versus NLR after first-line chemotherapy. Changes in NLR predicted the

The prognostic value of NLR is retained in metastatic PDAC. In treatment-naïve patients diagnosed with metastatic PDAC, NLR was significantly associated with survival, and multivariate analysis identified NLR as an independent prognostic factor. In addition, NLR also predicted the efficacy of oxaliplatin treatment [36]. In 39 patients with locally advanced unresectable and metastatic PDAC treated with gemcitabine and paclitaxel, higher NLR was associated with lower overall survival [37]. In similar bur larger study group comprising 261 patients with inoperable pancreatic cancer (both metastatic and locally advanced cases), high NLR (≥5) was an independent prognostic factor for worse cancer specific survival, as confirmed by p < 0.001 [25]. High NLR was associated with worse overall survival in the general group of PDAC patients, in metastatic cases and in those who had distant metastasis but also received chemotherapy [38]. Radiofrequency ablation (combined with systemic chemotherapy) for hepatic oligometastatic pancreatic cancer was associated with worse survival in patients having elevated NLR (≥2.5). In this clinical situation, NLR was confirmed as an independent predictive factor, along with cancer location in pancreatic head and diameter of

In 306 patients receiving palliative chemotherapy, NLR ≥ 5 was associated with shorter overall survival. In addition, multivariate analysis identified the independent predictive value of NLR [40]. Similarly, prognostic value of NLR in patients receiving palliative chemotherapy was reported by Xue et al., [41]. In patients undergoing gastroenterostomy for advanced pancreatic cancer, high NLR (≥4) was associated with shorter survival: 3.4 versus 9.4 months; p < 0.001 [42]. Thus, low NLR might be useful to identify those who have higher benefit from

Several meta-analyses have been devoted to NLR in pancreatic cancer. Zhou et al. [43] carried out a meta-analysis of 43 cohort studies containing 8252 patients and concluded that high NLR was significantly associated with worse overall survival (hazard ratio (HR) = 1.81; 95% confidence interval (CI): 1.59–2.05; p < 0.001) and cancer-free survival: HR = 1.66; 95%

CI:1.17–2.35; p = 0.005 [43]. Similar findings were reported by Cheng et al. [44].

ated with significantly shorter median survival: 6.9 versus 8.5 months; p = 0.0057 [35].

[8] in parallel to the abovementioned study [32].

efficacy of chemotherapy and the outcome [8].

the metastasis [39].

palliative surgery.

However, negative observations have also been reported. In a reliably large study group of 217 surgically treated PDAC patients, overall survival was significantly associated with age, adjuvant treatment, cancer invasion in blood vessels and lymphatics, R1 and pTN while NLR was not predictive of OS [28]. Assessing 379 consecutive patients who underwent curative resection for pancreatic cancer, no significant differences in overall survival were found in patients showing high versus low NLR although another SIR marker, the Glasgow prognostic score was confirmed as a significant predictor of survival [20].

A meta-analysis of eight studies including 1519 patients with resectable pancreatic cancer has been recently carried out by Mowbray et al. [29]. The pooled data confirm association between high NLR and low overall survival: HR = 1.77; 95% CI: 1.45–2.15; p < 0.01 [29]. In a systematic review of resectable pancreatic cancer, 10 studies were eligible and 8 had reported NLR. Significant association with survival was found in three of them [5].

The prognostic value of NLR has also been investigated in advanced and metastatic PDAC cases. In a large cohort of patients (497) diagnosed with locally advanced pancreatic cancer and treated by neoadjuvant or definitive chemoradiotherapy, elevated NLR was significantly associated with worse 1-year overall survival and 1-year progression free survival rates. In this study, the median value was selected as the cut-off threshold. Patients presenting with low NLR (<1.89), had 1-year survival rate of 73.2% and 1-year progression free survival rate of 43.9%, contrasting with those having high NLR (≥1.89): 60.8% survived at least 1-year and 31.3% were free of progression at least for 1-year (both p < 0.001) as reported by Lee et al., [30]. In advanced pancreatic cancer, high NLR was a significant independent prognostic marker for shorter survival. The median survival was 2.6 versus 8.5 months in patients having NLR ≥ 5 versus NLR < 5 [31]. In 132 patients who underwent chemotherapy for advanced pancreatic cancer, high baseline NLR (>2.78, based on ROC) and high value after two cycles of chemotherapy were associated with lower overall survival. In addition, even worse prognosis was identified in patients who had both these factors. The overall survival was 15.2 months in patients who had low baseline NLR and did not experience the increase of NLR after two cycles of chemotherapy, but only 3.8 months in those having both undesirable factors: high NLR and increase during treatment. If only baseline NLR was high, the survival was 7.6 months. If only NLR increase was observed, the survival was 6.8 months [32]. High NRL retained a prognostic value in elderly (at least 75 years of age) patients who underwent chemotherapy for unresectable PDAC [33].

Interesting findings have been reported on NLR in patients who underwent preoperative chemoradiotherapy followed by complete surgical resection. Such research design allows morphological evaluation of the response to preoperative treatment. Poor response was associated with higher pre-treatment NLR [34]. To predict efficacy of chemotherapy, both pre-treatment NLR and its dynamics are considered important. Thus, low baseline NLR and low NLR after first-line chemotherapy were associated with higher efficacy of chemotherapy [8] in parallel to the abovementioned study [32].

In most studies, preoperative NLR has been assessed. However, the patient's immune status after the surgery might be as important. Indeed, postoperative NLR, evaluated 1 month after the surgery, was shown to have a prognostic value for overall and recurrence-free survival. Comparing the patients with NLR ≥ 3 versus NLR < 3.0, the 1-year survival rate was 42.6 versus 81.9% and 3-year survival rate: 7.3 versus 33.9% (p < 0.001). Notably, the differences were confirmed to be statistically significant despite relatively small study group comprising

However, negative observations have also been reported. In a reliably large study group of 217 surgically treated PDAC patients, overall survival was significantly associated with age, adjuvant treatment, cancer invasion in blood vessels and lymphatics, R1 and pTN while NLR was not predictive of OS [28]. Assessing 379 consecutive patients who underwent curative resection for pancreatic cancer, no significant differences in overall survival were found in patients showing high versus low NLR although another SIR marker, the Glasgow prognostic

A meta-analysis of eight studies including 1519 patients with resectable pancreatic cancer has been recently carried out by Mowbray et al. [29]. The pooled data confirm association between high NLR and low overall survival: HR = 1.77; 95% CI: 1.45–2.15; p < 0.01 [29]. In a systematic review of resectable pancreatic cancer, 10 studies were eligible and 8 had reported

The prognostic value of NLR has also been investigated in advanced and metastatic PDAC cases. In a large cohort of patients (497) diagnosed with locally advanced pancreatic cancer and treated by neoadjuvant or definitive chemoradiotherapy, elevated NLR was significantly associated with worse 1-year overall survival and 1-year progression free survival rates. In this study, the median value was selected as the cut-off threshold. Patients presenting with low NLR (<1.89), had 1-year survival rate of 73.2% and 1-year progression free survival rate of 43.9%, contrasting with those having high NLR (≥1.89): 60.8% survived at least 1-year and 31.3% were free of progression at least for 1-year (both p < 0.001) as reported by Lee et al., [30]. In advanced pancreatic cancer, high NLR was a significant independent prognostic marker for shorter survival. The median survival was 2.6 versus 8.5 months in patients having NLR ≥ 5 versus NLR < 5 [31]. In 132 patients who underwent chemotherapy for advanced pancreatic cancer, high baseline NLR (>2.78, based on ROC) and high value after two cycles of chemotherapy were associated with lower overall survival. In addition, even worse prognosis was identified in patients who had both these factors. The overall survival was 15.2 months in patients who had low baseline NLR and did not experience the increase of NLR after two cycles of chemotherapy, but only 3.8 months in those having both undesirable factors: high NLR and increase during treatment. If only baseline NLR was high, the survival was 7.6 months. If only NLR increase was observed, the survival was 6.8 months [32]. High NRL retained a prognostic value in elderly (at least 75 years of age) patients who underwent

Interesting findings have been reported on NLR in patients who underwent preoperative chemoradiotherapy followed by complete surgical resection. Such research design allows

score was confirmed as a significant predictor of survival [20].

chemotherapy for unresectable PDAC [33].

NLR. Significant association with survival was found in three of them [5].

86 patients [27].

10 Advances in Pancreatic Cancer

In patients receiving stereotactic radiotherapy for advanced PDAC, high NLR (>5) was associated with significantly shorter median survival: 6.9 versus 8.5 months; p = 0.0057 [35].

Again, the prognostic role of NLR in advanced pancreatic cancer has not always been confirmed. In 122 patients, undergoing chemotherapy for inoperable pancreatic cancer, both high and low NLR was associated with the same median survival of 10 months. In the same study, the dynamics of NLR still predicted outcomes although the biological difference was tiny: the median overall was 10 versus 11 months; p < 0.001. The dynamics was assessed as the ratio of pre-treatment NLR versus NLR after first-line chemotherapy. Changes in NLR predicted the efficacy of chemotherapy and the outcome [8].

The prognostic value of NLR is retained in metastatic PDAC. In treatment-naïve patients diagnosed with metastatic PDAC, NLR was significantly associated with survival, and multivariate analysis identified NLR as an independent prognostic factor. In addition, NLR also predicted the efficacy of oxaliplatin treatment [36]. In 39 patients with locally advanced unresectable and metastatic PDAC treated with gemcitabine and paclitaxel, higher NLR was associated with lower overall survival [37]. In similar bur larger study group comprising 261 patients with inoperable pancreatic cancer (both metastatic and locally advanced cases), high NLR (≥5) was an independent prognostic factor for worse cancer specific survival, as confirmed by p < 0.001 [25]. High NLR was associated with worse overall survival in the general group of PDAC patients, in metastatic cases and in those who had distant metastasis but also received chemotherapy [38]. Radiofrequency ablation (combined with systemic chemotherapy) for hepatic oligometastatic pancreatic cancer was associated with worse survival in patients having elevated NLR (≥2.5). In this clinical situation, NLR was confirmed as an independent predictive factor, along with cancer location in pancreatic head and diameter of the metastasis [39].

In 306 patients receiving palliative chemotherapy, NLR ≥ 5 was associated with shorter overall survival. In addition, multivariate analysis identified the independent predictive value of NLR [40]. Similarly, prognostic value of NLR in patients receiving palliative chemotherapy was reported by Xue et al., [41]. In patients undergoing gastroenterostomy for advanced pancreatic cancer, high NLR (≥4) was associated with shorter survival: 3.4 versus 9.4 months; p < 0.001 [42]. Thus, low NLR might be useful to identify those who have higher benefit from palliative surgery.

Several meta-analyses have been devoted to NLR in pancreatic cancer. Zhou et al. [43] carried out a meta-analysis of 43 cohort studies containing 8252 patients and concluded that high NLR was significantly associated with worse overall survival (hazard ratio (HR) = 1.81; 95% confidence interval (CI): 1.59–2.05; p < 0.001) and cancer-free survival: HR = 1.66; 95% CI:1.17–2.35; p = 0.005 [43]. Similar findings were reported by Cheng et al. [44].

#### **2.2. NLR and cancer burden**

### *2.2.1. NLR and local tumour features: pT and other traits*

If NLR in particular and SIR in general are mostly dictated by the events in cancer stroma, NLR should correlate with cancer burden, reflected by pT or cancer size. However, the data are controversial. Thus, in a study of 442 patients undergoing surgical treatment for pancreatic cancer, there was no association between NLR and tumour size or pT. No correlation was found with perineural invasion, involvement of resection margins, and invasion into blood or lymphatic vessels [21]. In contrast, high NLR (≥2) was significantly associated with pT and grade among 381 patients treated by curative resection [23]. In a recent meta-analysis of 8252 cases, lower NLR was observed in patients having smaller (p = 0.0007), better differentiated (p = 0.003) tumours at earlier (p = 0.02) stage [43].

persons is not the model to make conclusions on the feasibility of NLR for early diagnostics. Currently, NLR has no role in the primary diagnostic algorithms for PDAC. However, it can

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SIR parameters have been proposed as markers of malignancy in pancreatic cystic neoplasms. Thus, in 245 patients with mucinous cystic pancreatic neoplasms, NLR ≥ 1.96 was significantly (p < 0.001) associated with invasive carcinoma [47]. In 318 surgically treated patients with pancreatic cystic neoplasms, high NLR was significantly associated with malignant tumour by univariate analysis. However, PLR was found to be superior by multivariate analysis [48]. Regarding intraductal papillary mucinous neoplasms (IPMNs), a trend to higher median NLR was observed in malignant cases: 2.23 versus 2.04 in benign cases. However, because of the rarity of IPMNs, only 60 patients were enrolled in the study, and the difference in medians did not reach statistical significance, reflected by p = 0.14. By the cut-off at 3.6, the prediction of malignant behaviour became significant. Still, the sensitivity was only 40% while the specificity reached 93%. By multivariate analysis, enhancement in a solid nodule was found to be superior in comparison with NLR ≥ 3.6 or height of mural nodule ≥11 mm [49]. Assessing 76 patients, higher NLR was reported in malignant than in benign IPMNs: 2.51 versus 2.01 [50]. In a large group of 272 surgically resected IPMNs, NLR exceeding 4.0 was an independent factor (by multivariate analysis), associated with invasive carcinoma. To enhance the predictive value, a nomogram was created incorporating NLR (>4.0) along with cyst size (>3 cm), identification of enhanced solid component, dilation of pancreatic duct (>5 mm) and the presence of jaundice [51]. In PDAC patients, significantly higher NLR has been reported than in

case of pancreatic neuroendocrine neoplasms or pancreatic IPMNs [52].

Smoking and a wide spectrum of non-oncological diseases are known to influence NLR. In patients affected by unresectable pancreatic cancer, smoking history significantly (p = 0.001)

PLR is the second best known cellular parameter characterising SIR. Similarly to NLR, most studies have concentrated on the prognostic value of PLR regarding the survival. Two meta-analyses have been published recently (2018), and both teams have reached very similar conclusions on the association between elevated PLR and worse overall survival. In a meta-analysis of 17 studies on PLR in pancreatic cancer, the negative prognostic role of high PLR was confirmed by hazard ratio for worse overall survival HR = 1.28; 95% CI: 1.17–1.40; p < 0.001 and worse progression-free survival HR = 1.27; 95% CI = 1.03–1.57; p = 0.03 [53]. In another meta-analysis of 17 studies (including 16 reports on association between PLR and overall survival in 3028 patients), high PLR also was found to be associated with worse overall survival HR = 1.22; 95% CI: 1.09–1.36; p < 0.001. Interestingly, the prognostic role was confirmed in the subgroup of Asians (HR = 1.22; 95% CI: 1.11–1.34; p < 0.001) but not

**2.4. Confounding factors in NLR assessment**

**3. PLR in pancreatic ductal adenocarcinoma**

correlated with higher NLR [8].

**3.1. PLR and survival**

assist to solve specific diagnostic questions.

#### *2.2.2. NLR and regional lymph node involvement: pN*

The association between NLR and regional lymph node status also is controversial. While some research teams have observed higher NLR values in patients affected by tumour metastases in regional lymph nodes, other studies have not confirmed these findings. NLR was associated with lymph node metastasis in the study of 159 surgically treated PDAC patients [45]. Similarly, high NLR (≥2) was significantly associated with pN among 381 patients treated by curative resection [23]. In contrast, no correlation was found between NLR and cancer spread to regional lymph nodes reflected by pN or with invasion into lymphatic vessels by Sierzega et al. [21], evaluating 442 surgically treated patients. In Austrian cohort of 110 surgically treated pancreatic cancer patients, NLR lacked correlation with stage [25].

#### *2.2.3. NLR and presence of distant metastasis: pM*

In contrast to the previous aspects of tumour burden, namely, pT, size or pN, there is almost general agreement that pM1 is associated with higher NLR.

In patients diagnosed with unresectable pancreatic cancer, high pre-treatment NLR significantly correlated with presence of liver metastases [8]. Distant metastases were significantly more frequently identified in patients presenting with high NLR (>5): 61.6 versus 30.1%; p < 0.0001 [38]. In advanced pancreatic cancer (including both metastatic and locally advanced cases), high NLR (≥5) correlated with the presence of metastatic disease [25]. The association between NLR and presence of distant metastases has also been confirmed by a meta-analysis by Yang et al., showing the HR = 1.69; 95% CI: 1.10–2.59; p = 0.016 [46].

#### **2.3. Diagnostic role of NLR in pancreatic tumours**

The diagnostics of PDAC is frequently a difficult issue. However, the close association between chronic pancreatitis and PDAC significantly limits the applicability of SIR for early diagnostics.

Baseline NLR in unresectable pancreatic cancer has been found to be significantly higher than in healthy controls: 3.81 versus 1.80; p < 0.001 [8]. Although the biological difference in the detected levels is remarkable, the comparison between advanced cancer and healthy persons is not the model to make conclusions on the feasibility of NLR for early diagnostics. Currently, NLR has no role in the primary diagnostic algorithms for PDAC. However, it can assist to solve specific diagnostic questions.

SIR parameters have been proposed as markers of malignancy in pancreatic cystic neoplasms. Thus, in 245 patients with mucinous cystic pancreatic neoplasms, NLR ≥ 1.96 was significantly (p < 0.001) associated with invasive carcinoma [47]. In 318 surgically treated patients with pancreatic cystic neoplasms, high NLR was significantly associated with malignant tumour by univariate analysis. However, PLR was found to be superior by multivariate analysis [48].

Regarding intraductal papillary mucinous neoplasms (IPMNs), a trend to higher median NLR was observed in malignant cases: 2.23 versus 2.04 in benign cases. However, because of the rarity of IPMNs, only 60 patients were enrolled in the study, and the difference in medians did not reach statistical significance, reflected by p = 0.14. By the cut-off at 3.6, the prediction of malignant behaviour became significant. Still, the sensitivity was only 40% while the specificity reached 93%. By multivariate analysis, enhancement in a solid nodule was found to be superior in comparison with NLR ≥ 3.6 or height of mural nodule ≥11 mm [49]. Assessing 76 patients, higher NLR was reported in malignant than in benign IPMNs: 2.51 versus 2.01 [50]. In a large group of 272 surgically resected IPMNs, NLR exceeding 4.0 was an independent factor (by multivariate analysis), associated with invasive carcinoma. To enhance the predictive value, a nomogram was created incorporating NLR (>4.0) along with cyst size (>3 cm), identification of enhanced solid component, dilation of pancreatic duct (>5 mm) and the presence of jaundice [51]. In PDAC patients, significantly higher NLR has been reported than in case of pancreatic neuroendocrine neoplasms or pancreatic IPMNs [52].

#### **2.4. Confounding factors in NLR assessment**

Smoking and a wide spectrum of non-oncological diseases are known to influence NLR. In patients affected by unresectable pancreatic cancer, smoking history significantly (p = 0.001) correlated with higher NLR [8].
