Cytokines and Pancreatic Ductal Adenocarcinoma: Exploring Their Relationship with Molecular Subtypes and Prognosis
Abstract
:1. Introduction
2. Results
2.1. Descriptive Analysis of Clinical and Analytical Variables
2.2. Analysis of the Relationship between the Analyzed Cytokines and Other Analytical Parameters with Molecular Subtypes
2.3. Survival Analysis of the Different Treatment Regimens Received and Relationship between the Molecular Subtype and Prognosis
2.4. Analysis of the Relationship between the Analyzed Cytokines and Survival
2.5. Analysis of the Relationship between the Analyzed Cytokines and Disease Stage at Diagnosis and Location of Metastases
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Clinical and Analytical Variables Included
4.3. Processing of Cytology Samples
4.4. Processing of Plasma Samples and Cytokine Analysis
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variables | Patients (%) |
---|---|
Sex | n 73 |
Male | 33 (45) |
Female | 40 (55) |
ECOG performance status at diagnosis | |
0 | 24 (33) |
1 | 45 (62) |
2 | 4 (5) |
Smoking history | |
Smoker | 21 (29) |
Former smoker | 25 (34) |
Never smoker | 27 (37) |
Diabetes mellitus | 26 (36) |
Chronic pancreatitis | 6 (8) |
Primary tumor location | |
Head | 41 (56) |
Body and tail | 32 (44) |
Stage | |
Localized/borderline | 12 (16) |
Locally advanced | 21 (29) |
Metastatic | 40 (55) |
Hemoglobin | |
Normal hemoglobin (≥12.5 in males and ≥11.8 in females) | 43 (58.9) |
Anemia grade 1 (Normal hemoglobin—Hb 10 gr/dL) | 28 (38.3) |
Anemia grade 2 (Hb 9.9 gr/dL—Hb 8 gr/dL) | 1 (1.4) |
Anemia grade 3 (Hb 7.9 gr/dL—Hb 6.5 gr/dL) | 1 (1.4) |
Platelets | |
<150.000/µL | 5 (6.8) |
≥150.000/µL | 68 (93.2) |
C-reactive protein (CRP) | |
>5 mg/L | 54 (74.0) |
≤5 mg/L | 19 (26.0) |
Neutrophil-to-lymphocyte ratio (NLR) | |
>Median | 37 (50.7) |
≤Median | 36 (49.3) |
Platelet-to-lymphocyte ratio (PLR) | |
>Median | 36 (49.3) |
≤Median | 37 (50.7) |
CA19-9 | |
>36 UI/mL | 49 (67.1) |
≤36 UI/mL | 24 (32.9) |
Molecular subtype | n 34 |
Classical | 17 (50) |
Basal-like | 9 (26) |
Mixed | 5 (15) |
Null | 3 (9) |
Cytokines | Univariate Analysis for PFS during First-Line | ||
---|---|---|---|
p-Value | HR | 95% CI | |
IL-1α | 0.011 | 1.004 | 1.001–1.006 |
IL-1β | 0.001 | 1.439 | 1.150–1.801 |
IL-6 | <0.001 | 1.016 | 1.008–1.023 |
IL-8 | 0.045 | 1.001 | 1.00003–1.003 |
IL-9 | 0.004 | 1.010 | 1.003–1.017 |
IL-10 | 0.880 | 0.997 | 0.954–1.041 |
IP-10 | 0.169 | 1.0001 | 0.999–1.0004 |
IL-15 | <0.001 | 1.210 | 1.110–1.318 |
IL-17A | 0.377 | 1.093 | 0.897–1.333 |
TGF-β1 | 0.305 | 1.00001 | 0.999–1.00004 |
TGF-β2 | 0.719 | 1.00005 | 0.999–1.0003 |
TGF-β3 | 0.486 | 0.998 | 0.993–1.003 |
TNF-α | 0.192 | 1.007 | 0.996–1.018 |
Cytokines | Univariate Analysis for OS | ||
p-Value | HR | 95% CI | |
IL-1α | 0.096 | 1.002 | 0.999–1.005 |
IL-1β | 0.023 | 1.298 | 1.036–1.626 |
IL-6 | 0.001 | 1.012 | 1.005–1.019 |
IL-8 | 0.058 | 1.001 | 0.999–1.003 |
IL-9 | 0.054 | 1.007 | 0.999–1.014 |
IL-10 | 0.717 | 1.008 | 0.967–1.050 |
IP-10 | 0.231 | 1.0001 | 0.999–1.0003 |
IL-15 | <0.001 | 1.189 | 1.086–1.302 |
IL-17A | 0.478 | 1.075 | 0.881–1.311 |
TGF-β1 | 0.146 | 1.00002 | 0.999–1.00005 |
TGF-β2 | 0.730 | 1.00005 | 0.999–1.0003 |
TGF-β3 | 0.320 | 0.997 | 0.992–1.003 |
TNF-α | 0.052 | 1.012 | 0.999–1.023 |
Multivariate Analysis for PFS during First-Line | |||
---|---|---|---|
Variables | p-Value | HR | 95% CI |
Initial model | |||
ECOG performance status | 0.200 | 1.62 | 0.77–3.41 |
Stage | 0.786 | 1.09 | 0.57–2.07 |
Chemotherapy regimen used during first-line treatment * | 0.406 | 1.31 | 0.68–2.51 |
CA19-9 levels above the upper limit of normal | 0.180 | 1.55 | 0.81–2.98 |
IL-6 (reference group < p25) | 0.676 | ||
| 0.276 | 1.65 | 0.67–4.07 |
| 0.289 | 1.67 | 0.64–4.35 |
| 0.322 | 1.81 | 0.55–5.92 |
IL-8 (reference group < p25) | 0.025 | ||
| 0.967 | 1.01 | 0.45–2.29 |
| 0.431 | 1.52 | 0.53–4.33 |
| 0.009 | 4.95 | 1.48–16.54 |
Final model | |||
ECOG performance status | 0.038 | 1.97 | 1.03–3.74 |
IL-8 (reference group < p25) | <0.001 | ||
| 0.848 | 1.07 | 0.51–2.23 |
| 0.130 | 1.80 | 0.84–3.85 |
| <0.001 | 7.92 | 3.22–19.48 |
Multivariate analysis for OS | |||
Variables | p-Value | HR | 95% CI |
Initial model | |||
ECOG performance status | 0.082 | 1.82 | 0.92–3.58 |
Stage | 0.721 | 0.89 | 0.48–1.65 |
Chemotherapy regimen used during first-line treatment * | 0.955 | 0.98 | 0.53–1.79 |
CA19-9 levels above the upper limit of normal | 0.071 | 1.83 | 0.94–3.56 |
IL-8 (reference group < p25) | 0.008 | ||
| 0.901 | 0.95 | 0.44–2.04 |
| 0.663 | 1.20 | 0.52–2.76 |
| 0.003 | 3.84 | 1.58–9.34 |
Final model | |||
ECOG performance status | 0.080 | 1.78 | 0.93–3.41 |
CA19-9 levels above the upper limit of normal | 0.064 | 1.86 | 0.96–3.59 |
IL-8 (reference group < p25) | 0.007 | ||
| 0.872 | 0.93 | 0.43–2.01 |
| 0.721 | 1.15 | 0.51–2.59 |
| 0.003 | 3.68 | 1.57–8.61 |
Cytokines | Localized/Borderline Disease | Locally Advanced Disease | Metastatic Disease | p-Value | ||||||
---|---|---|---|---|---|---|---|---|---|---|
p25 | p50 | p75 | p25 | p50 | p75 | p25 | p50 | p75 | ||
IL-1α | 0.80 | 1.67 | 3.15 | 0.45 | 0.76 | 1.03 | 0.58 | 1.00 | 3.43 | 0.128 |
IL-1β | 1.25 | 1.79 | 2.25 | 1.21 | 1.51 | 1.99 | 1.12 | 1.37 | 1.80 | 0.481 |
IL-6 | 1.35 | 2.24 | 4.56 | 1.95 | 5.48 | 11.30 | 2.29 | 6.29 | 20.20 | 0.112 |
IL-8 | 6.45 | 9.58 | 20.97 | 8.91 | 15.40 | 22.92 | 11.41 | 30.81 | 117 | 0.008 |
IL-9 | 1.35 | 3.45 | 6.98 | 1.73 | 2.73 | 6.15 | 1.53 | 2.03 | 3.18 | 0.557 |
IL-10 | 3.50 | 5.56 | 6.76 | 3.33 | 4.27 | 5.41 | 2.74 | 3.86 | 6.85 | 0.737 |
IP-10 | 369.00 | 437.50 | 958.25 | 444 | 637 | 1502 | 415 | 661 | 1087.25 | 0.444 |
IL-15 | 3.16 | 4.95 | 5.75 | 2.73 | 3.62 | 4.59 | 2.90 | 4.09 | 5.45 | 0.432 |
IL-17A | 1.42 | 2.16 | 2.89 | 1.55 | 2.17 | 2.90 | 1.33 | 1.55 | 2.02 | 0.057 |
TGF-β1 | 8102.75 | 12,553.50 | 32,262 | 6581.50 | 15,285 | 21,542 | 8243 | 14,496.50 | 21,854 | 0.791 |
TGF-β2 | 409.00 | 566.00 | 1629.75 | 330 | 559 | 1573.50 | 428 | 639 | 1099.25 | 0.944 |
TGF-β3 | 30.92 | 39.94 | 87.89 | 36.62 | 72.36 | 132 | 33.30 | 63.71 | 72.36 | 0.417 |
TNF-α | 8.67 | 12.09 | 25.18 | 8.16 | 17.69 | 23.52 | 10.70 | 16.31 | 30.21 | 0.475 |
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Gutierrez-Sainz, L.; Heredia-Soto, V.; Rodríguez-García, A.M.; Crespo Sánchez, M.G.; Serrano-Olmedo, M.G.; Molero-Luis, M.; Losantos-García, I.; Ghanem, I.; Pérez-Wert, P.; Custodio, A.; et al. Cytokines and Pancreatic Ductal Adenocarcinoma: Exploring Their Relationship with Molecular Subtypes and Prognosis. Int. J. Mol. Sci. 2024, 25, 9368. https://doi.org/10.3390/ijms25179368
Gutierrez-Sainz L, Heredia-Soto V, Rodríguez-García AM, Crespo Sánchez MG, Serrano-Olmedo MG, Molero-Luis M, Losantos-García I, Ghanem I, Pérez-Wert P, Custodio A, et al. Cytokines and Pancreatic Ductal Adenocarcinoma: Exploring Their Relationship with Molecular Subtypes and Prognosis. International Journal of Molecular Sciences. 2024; 25(17):9368. https://doi.org/10.3390/ijms25179368
Chicago/Turabian StyleGutierrez-Sainz, Laura, Victoria Heredia-Soto, Ana Margarita Rodríguez-García, María Gema Crespo Sánchez, María Gemma Serrano-Olmedo, Marta Molero-Luis, Itsaso Losantos-García, Ismael Ghanem, Pablo Pérez-Wert, Ana Custodio, and et al. 2024. "Cytokines and Pancreatic Ductal Adenocarcinoma: Exploring Their Relationship with Molecular Subtypes and Prognosis" International Journal of Molecular Sciences 25, no. 17: 9368. https://doi.org/10.3390/ijms25179368