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Article ; Online: Metformin boosts anti-tumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study.

van Eijck, Casper W F / Vadgama, Disha / van Eijck, Casper H J / Wilmink, Johanna W

Journal of the National Cancer Institute

2024

Abstract: Background: Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient ...

Abstract	Background: Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in PDAC tumors. Methods: We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens. Results: Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI, 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < 0.001). Conclusion: This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring anti-tumor immunity.
Language	English
Publishing date	2024-03-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djae070
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Article ; Online: Fat-Soluble Vitamin Deficiencies and Disruption of the Immune System in Pancreatic Cancer: A Vicious Cycle.

Aziz, Mohammad Hosein / van der Meulen, Jan / Mustafa, Dana A M / van Eijck, Casper H J

Pancreas

2022 Volume 51, Issue 8, Page(s) 923–929

Abstract: Abstract: Pancreatic ductal adenocarcinoma (PDAC) is currently an increasing contributor to cancer-related mortality. Despite advances in cancer treatment, PDAC survival rates have remained roughly unchanged over the years. Specifically, late diagnosis ... ...

Abstract	Abstract: Pancreatic ductal adenocarcinoma (PDAC) is currently an increasing contributor to cancer-related mortality. Despite advances in cancer treatment, PDAC survival rates have remained roughly unchanged over the years. Specifically, late diagnosis and insensitivity to currently available therapeutic regimens have been identified as the main causes for its poor survival. Pancreatic exocrine insufficiency (PEI) is a typical complication associated with PDAC diagnosis and pancreatic surgery. Pancreatic exocrine insufficiency, a major contributor to maldigestion in PDAC, is often not treated because it remains undetected because of lack of overt signs and symptoms. In this review, we will focus on the major consequences of PEI, including the inadequacy of lipase excretion, which results in deficiency of fat-soluble vitamins. Because PDAC is known for its immune-high jacking mechanisms, we describe key features in which deficiencies of fat-soluble vitamins may contribute to the aggressive biological behavior and immune evasion in PDAC. Because PEI has been shown to worsen survival rates in patients with PDAC, detecting PEI and the related fat-soluble vitamin deficits at the time of PDAC diagnosis is critical. Moreover, timely supplementation of pancreatic enzymes and fat-soluble vitamins may improve outcomes for PDAC patients.
MeSH term(s)	Humans ; Vitamins/therapeutic use ; Exocrine Pancreatic Insufficiency/etiology ; Exocrine Pancreatic Insufficiency/complications ; Pancreatic Neoplasms/therapy ; Pancreatic Neoplasms/complications ; Carcinoma, Pancreatic Ductal/therapy ; Carcinoma, Pancreatic Ductal/complications ; Immune System ; Avitaminosis/complications ; Pancreatic Neoplasms
Chemical Substances	Vitamins
Language	English
Publishing date	2022-11-04
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	632831-3
ISSN	1536-4828 ; 0885-3177
ISSN (online)	1536-4828
ISSN	0885-3177
DOI	10.1097/MPA.0000000000002128
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Zs.A 2160: Show issues

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Article ; Online: ASO Author Reflections: Nationwide Experience on Locally Advanced Pancreatic Cancer Surgery After Induction Chemotherapy in the Netherlands: A Stepping Stone for the PREOPANC-4 Trial.

Stoop, Thomas F / Seelen, Leonard W F / van 't Land, Freek R / van Eijck, Casper H J / van Santvoort, Hjalmar C / Besselink, Marc G

Annals of surgical oncology

2023 Volume 31, Issue 4, Page(s) 2658–2659

MeSH term(s)	Humans ; Induction Chemotherapy ; Neoadjuvant Therapy ; Netherlands ; Pancreas/surgery ; Pancreatectomy ; Pancreatic Hormones ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/surgery ; Clinical Trials as Topic
Chemical Substances	Pancreatic Hormones
Language	English
Publishing date	2023-12-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1200469-8
ISSN	1534-4681 ; 1068-9265
ISSN (online)	1534-4681
ISSN	1068-9265
DOI	10.1245/s10434-023-14704-9
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Zs.A 4042: Show issues

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Article ; Online: Enhanced antitumour immunity following neoadjuvant chemoradiotherapy mediates a favourable prognosis in women with resected pancreatic cancer.

van Eijck, Casper W F / Mustafa, Dana A M / Vadgama, Disha / de Miranda, Noel F C C / Groot Koerkamp, Bas / van Tienhoven, Geertjan / van der Burg, Sjoerd H / Malats, Núria / van Eijck, Casper H J

Gut

2024 Volume 73, Issue 2, Page(s) 311–324

Abstract: Background: This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant ... ...

Abstract	Background: This study investigates sex disparities in clinical outcomes and tumour immune profiles in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection preceded by gemcitabine-based neoadjuvant chemoradiotherapy (nCRT). Methods: Patients originated from the PREOPANC randomised controlled trial. Upfront surgery was performed in 82 patients, and 66 received nCRT before resection. The impact of sex on overall survival (OS) was investigated using Cox proportional hazards models. The immunological landscape within the tumour microenvironment (TME) was mapped using transcriptomic and spatial proteomic profiling. Results: The 5-year OS rate differed between the sexes following resection preceded by nCRT, with 43% for women compared with 22% for men. In multivariate analysis, the female sex was a favourable independent prognostic factor for OS only in the nCRT group (HR 0.19; 95% CI 0.07 to 0.52). Multivariate heterogeneous treatment effects analysis revealed a significant interaction between sex and treatment, implying increased nCRT efficacy among women with resected PDAC. The TME of women contained fewer protumoural CD163+MRC1+M2 macrophages than that of men after nCRT, as indicated by transcriptomic and validated using spatial proteomic profiling. Conclusion: PDAC tumours of women are more sensitive to gemcitabine-based nCRT, resulting in longer OS after resection compared with men. This may be due to enhanced immunity impeding the infiltration of protumoral M2 macrophages into the TME. Our findings highlight the importance of considering sex disparities and mitigating immunosuppressive macrophage polarisation for personalised PDAC treatment.
MeSH term(s)	Male ; Humans ; Female ; Neoadjuvant Therapy ; Gemcitabine ; Proteomics ; Prognosis ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/therapy ; Carcinoma, Pancreatic Ductal/pathology ; Retrospective Studies ; Tumor Microenvironment
Chemical Substances	Gemcitabine
Language	English
Publishing date	2024-01-05
Publishing country	England
Document type	Journal Article
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2023-330480
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Zs.A 160: Show issues

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Article ; Online: A liquid biomarker signature of inflammatory proteins accurately predicts early pancreatic cancer progression during FOLFIRINOX chemotherapy.

van Eijck, Casper W F / Sabroso-Lasa, Sergio / Strijk, Gaby J / Mustafa, Dana A M / Fellah, Amine / Koerkamp, Bas Groot / Malats, Núria / van Eijck, Casper H J

Neoplasia (New York, N.Y.)

2024 Volume 49, Page(s) 100975

Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) is often treated with FOLFIRINOX, a chemotherapy associated with high toxicity rates and variable efficacy. Therefore, it is crucial to identify patients at risk of early progression during treatment. ... ...

Abstract	Background: Pancreatic ductal adenocarcinoma (PDAC) is often treated with FOLFIRINOX, a chemotherapy associated with high toxicity rates and variable efficacy. Therefore, it is crucial to identify patients at risk of early progression during treatment. This study aims to explore the potential of a multi-omics biomarker for predicting early PDAC progression by employing an in-depth mathematical modeling approach. Methods: Blood samples were collected from 58 PDAC patients undergoing FOLFIRINOX before and after the first cycle. These samples underwent gene (GEP) and inflammatory protein expression profiling (IPEP). We explored the predictive potential of exclusively IPEP through Stepwise (Backward) Multivariate Logistic Regression modeling. Additionally, we integrated GEP and IPEP using Bayesian Kernel Regression modeling, aiming to enhance predictive performance. Ultimately, the FOLFIRINOX IPEP (FFX-IPEP) signature was developed. Results: Our findings revealed that proteins exhibited superior predictive accuracy than genes. Consequently, the FFX-IPEP signature consisted of six proteins: AMN, BANK1, IL1RL2, ITGB6, MYO9B, and PRSS8. The signature effectively identified patients transitioning from disease control to progression early during FOLFIRINOX, achieving remarkable predictive accuracy with an AUC of 0.89 in an independent test set. Importantly, the FFX-IPEP signature outperformed the conventional CA19-9 tumor marker. Conclusions: Our six-protein FFX-IPEP signature holds solid potential as a liquid biomarker for the early prediction of PDAC progression during toxic FOLFIRINOX chemotherapy. Further validation in an external cohort is crucial to confirm the utility of the FFX-IPEP signature. Future studies should expand to predict progression under different chemotherapies to enhance the guidance of personalized treatment selection in PDAC.
MeSH term(s)	Humans ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Bayes Theorem ; Fluorouracil/therapeutic use ; Carcinoma, Pancreatic Ductal/diagnosis ; Carcinoma, Pancreatic Ductal/drug therapy ; Carcinoma, Pancreatic Ductal/genetics ; Biomarkers, Tumor ; Irinotecan ; Oxaliplatin ; Leucovorin
Chemical Substances	folfirinox ; Fluorouracil (U3P01618RT) ; Biomarkers, Tumor ; Irinotecan (7673326042) ; Oxaliplatin (04ZR38536J) ; Leucovorin (Q573I9DVLP)
Language	English
Publishing date	2024-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2024.100975
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Zs.A 5203: Show issues

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Article ; Online: Association of blood cell-based inflammatory markers with gut microbiota and cancer incidence in the Rotterdam study.

Najjary, Shiva / Kros, Johan M / Stricker, Bruno H / Ruiter, Rikje / Shuai, Yu / Kraaij, Robert / Van Steen, Kristel / van der Spek, Peter / Van Eijck, Casper H J / Ikram, M Arfan / Ahmad, Shahzad

Cancer medicine

2024 Volume 13, Issue 3, Page(s) e6860

Abstract: The immune response-gut microbiota interaction is implicated in various human diseases, including cancer. Identifying the link between the gut microbiota and systemic inflammatory markers and their association with cancer will be important for our ... ...

Abstract	The immune response-gut microbiota interaction is implicated in various human diseases, including cancer. Identifying the link between the gut microbiota and systemic inflammatory markers and their association with cancer will be important for our understanding of cancer etiology. The current study was performed on 8090 participants from the population-based Rotterdam study. We found a significant association (false discovery rate [FDR] ≤0.05) between lymphocytes and three gut microbial taxa, namely the family Streptococcaceae, genus Streptococcus, and order Lactobacillales. In addition, we identified 95 gut microbial taxa that were associated with inflammatory markers (p < 0.05). Analyzing the cancer data, we observed a significant association between higher systemic immune-inflammation index (SII) levels at baseline (hazard ratio (HR): 1.65 [95% confidence interval (CI); 1.10-2.46, p ≤ 0.05]) and a higher count of lymphocytes (HR: 1.38 [95% CI: 1.15-1.65, p ≤ 0.05]) and granulocytes (HR: 1.69 [95% CI: 1.40-2.03, p ≤ 0.05]) with increased risk of lung cancer after adjusting for age, sex, body mass index (BMI), and study cohort. This association was lost for SII and lymphocytes after additional adjustment for smoking (SII = HR:1.46 [95% CI: 0.96-2.22, p = 0.07] and lymphocytes = HR: 1.19 [95% CI: 0.97-1.46, p = 0.08]). In the stratified analysis, higher count of lymphocyte and granulocytes at baseline were associated with an increased risk of lung cancer in smokers after adjusting for age, sex, BMI, and study cohort (HR: 1.33 [95% CI: 1.09-1.62, p ≤0.05] and HR: 1.57 [95% CI: 1.28-1.92, p ≤0.05], respectively). Our study revealed a positive association between gut microbiota, higher SII levels, and higher lymphocyte and granulocyte counts, with an increased risk of developing lung cancer.
MeSH term(s)	Humans ; Gastrointestinal Microbiome ; Incidence ; Lung Neoplasms ; Body Mass Index ; Inflammation/epidemiology ; Blood Cells
Language	English
Publishing date	2024-02-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.6860
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Article ; Online: Rintatolimod in Advanced Pancreatic Cancer enhances Anti-Tumor Immunity through Dendritic Cell-Mediated T Cell Responses.

van Eijck, Casper W F / El Haddaoui, Hassana / Kucukcelebi, Songul / Vadgama, Disha / Fellah, Amine / Mustafa, Dana A M / Aerts, Joachim G J V / van Eijck, Casper H J / Willemsen, Marcella

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: Purpose: Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual ... ...

Abstract	Purpose: Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the anti-tumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of advanced PDAC patients. Patients and methods: Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunological factors on survival outcomes was assessed through univariate Cox proportional hazards models. Results: Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1s) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronounced DC and T cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1. Conclusions: This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunological tolerance by enhancing anti-tumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes.
Language	English
Publishing date	2024-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-4085
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Zs.A 4223: Show issues

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Article: Trends in Staging, Treatment, and Survival in Colorectal Cancer Between 1990 and 2014 in the Rotterdam Study.

Lavrijssen, Birgit D A / Ruiter, Rikje / Fest, Jesse / Ikram, Mohammad A / Stricker, Bruno H / van Eijck, Casper H J

Frontiers in oncology

2022 Volume 12, Page(s) 849951

Abstract: Background: This study aims to assess trends in patient-related factors and treatment strategies in Dutch colorectal cancer (CRC) patients and their effect on survival.: Methods: Data were obtained from the Rotterdam study, an ongoing population- ... ...

Abstract	Background: This study aims to assess trends in patient-related factors and treatment strategies in Dutch colorectal cancer (CRC) patients and their effect on survival. Methods: Data were obtained from the Rotterdam study, an ongoing population-based study of individuals aged ≥45 years. Between 1990 and 2014, incident, pathology-confirmed CRC cases were divided into two groups based on date of diagnosis (either before or after January 1, 2003). Patient characteristics, initial treatment, and date of mortality were collected. Analyses were performed using Kaplan-Meier and Cox proportional hazard models. Results: Of 14,928 individuals, 272 developed colon cancer and 124 rectal cancer. Median follow-up was 13.2 years. Patients diagnosed after January 1, 2003 were treated chemotherapeutically more often than those diagnosed prior to this date in colon cancer (28.6% vs. 9.1%, Conclusion: Chemotherapeutic agents and radiotherapy are increasingly used in CRC patients. Survival in rectal cancer improved, whereas in colon cancer this was not observed.
Language	English
Publishing date	2022-02-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.849951
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Article ; Online: Resectie van longmetastasen gerechtvaardigd?

Detillon, D E M A / van Eijck, Casper H J / Veen, Eelco J

Nederlands tijdschrift voor geneeskunde

2019 Volume 163

Abstract: Until recently, patients with cancer and distant metastases were considered incurable. However, nowadays, some of these patients are eligible for curative-intent therapy. Surgery of metastases is becoming an increasingly important part of this ever- ... ...

Title translation	Is surgical treatment of pulmonary metastases justified?
Abstract	Until recently, patients with cancer and distant metastases were considered incurable. However, nowadays, some of these patients are eligible for curative-intent therapy. Surgery of metastases is becoming an increasingly important part of this ever-evolving therapy. The introduction of minimally invasive surgical techniques has resulted in more resections being performed of pulmonary metastases, even in elderly patients. Low postoperative morbidity and mortality rates have been observed after pulmonary metastasectomy. This is also true for elderly patients as age has not been linked to postoperative morbidity. Long-term survival is better for patients undergoing pulmonary metastasectomy compared to non-surgically treated patients. However, selection bias plays an important role as only relatively fit patients can tolerate surgery and their prognosis is therefore better from the onset. The question therefore remains whether pulmonary metastasectomy, a non-evidence-based treatment, is justified.
MeSH term(s)	Aged ; Disease-Free Survival ; Female ; Humans ; Lung Neoplasms/pathology ; Lung Neoplasms/secondary ; Lung Neoplasms/surgery ; Male ; Metastasectomy/statistics & numerical data ; Middle Aged ; Pneumonectomy/statistics & numerical data ; Prognosis ; Retrospective Studies ; Survival Rate
Language	Dutch
Publishing date	2019-06-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	82073-8
ISSN	1876-8784 ; 0028-2162
ISSN (online)	1876-8784
ISSN	0028-2162
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Article ; Online: Neoadjuvant chemotherapy is associated with suppression of the B cell-centered immune landscape in pancreatic ductal adenocarcinoma.

Rupp, Luise / Dietsche, Ina / Kießler, Maximilian / Sommer, Ulrich / Muckenhuber, Alexander / Steiger, Katja / van Eijck, Casper W F / Richter, Leonard / Istvanffy, Rouzanna / Jäger, Carsten / Friess, Helmut / van Eijck, Casper H J / Demir, Ihsan Ekin / Reyes, Carmen Mota / Schmitz, Marc

Frontiers in immunology

2024 Volume 15, Page(s) 1378190

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages and associated with early distant metastasis and poor survival. Besides clinical factors, the tumor microenvironment (TME) emerged as a crucial determinant of patient ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages and associated with early distant metastasis and poor survival. Besides clinical factors, the tumor microenvironment (TME) emerged as a crucial determinant of patient survival and therapy response in many tumors, including PDAC. Thus, the presence of tumor-infiltrating lymphocytes and the formation of tertiary lymphoid structures (TLS) is associated with longer survival in PDAC. Although neoadjuvant therapy (NeoTx) has improved the management of locally advanced tumors, detailed insight into its effect on various TME components is limited. While a remodeling towards a proinflammatory state was reported for PDAC-infiltrating T cells, the effect of NeoTx on B cell subsets, including plasma cells, and TLS formation is widely unclear. We thus investigated the frequency, composition, and spatial distribution of PDAC-infiltrating B cells in primary resected (PR) versus neoadjuvant-treated patients using a novel multiplex immunohistochemistry panel. The NeoTx group displayed significantly lower frequencies of pan B cells, GC B cells, plasmablasts, and plasma cells, accompanied by a reduced abundance of TLS. This finding was supported by bulk RNA-sequencing analysis of an independent fresh frozen tissue cohort, which revealed that major B cell pathways were downregulated in the NeoTx group. We further observed that plasma cells frequently formed aggregates that localized close to TLS and that TLS
MeSH term(s)	Humans ; Neoadjuvant Therapy/methods ; Pancreatic Neoplasms/drug therapy ; Carcinoma, Pancreatic Ductal/drug therapy ; B-Lymphocytes ; T-Lymphocytes/pathology ; Tumor Microenvironment
Language	English
Publishing date	2024-04-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1378190
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