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Article ; Online: Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes.

de Koning, Willem / Latifi, Diba / Li, Yunlei / van Eijck, Casper H J / Stubbs, Andrew P / Mustafa, Dana A M

2021 Volume 12, Page(s) 649061

Abstract: The immune response affects tumor biological behavior and progression. The specific immune characteristics of pancreatic ductal adenocarcinoma (PDAC) can determine the metastatic abilities of cancerous cells and the survival of patients. Therefore, it is ...

Abstract	The immune response affects tumor biological behavior and progression. The specific immune characteristics of pancreatic ductal adenocarcinoma (PDAC) can determine the metastatic abilities of cancerous cells and the survival of patients. Therefore, it is important to characterize the specific immune landscape in PDAC tissue samples, and the effect of various types of therapy on that immune composition. Previously, a set of marker genes was identified to assess the immune cell composition in different types of cancer tissue samples. However, gene expression and subtypes of immune cells may vary across different types of cancers. The aim of this study was to provide a method to identify immune cells specifically in PDAC tissue samples. The method is based on defining a specific set of marker genes expressed by various immune cells in PDAC samples. A total of 90 marker genes were selected and tested for immune cell type-specific definition in PDAC; including 43 previously used, and 47 newly selected marker genes. The immune cell-type specificity was checked mathematically by calculating the "pairwise similarity" for all candidate genes using the PDAC RNA-sequenced dataset available at The Cancer Genome Atlas. A set of 55 marker genes that identify 22 different immune cell types for PDAC was created. To validate the method and the set of marker genes, an independent mRNA expression dataset of 24 samples of PDAC patients who received various types of (neo)adjuvant treatments was used. The results showed that by applying our method we were able to identify PDAC specific marker genes to characterize immune cell infiltration in tissue samples. The method we described enabled identifying different subtypes of immune cells that were affected by various types of therapy in PDAC patients. In addition, our method can be easily adapted and applied to identify the specific immune landscape in various types of tissue samples.
MeSH term(s)	Biomarkers, Tumor/genetics ; Biomarkers, Tumor/immunology ; Biomarkers, Tumor/metabolism ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/immunology ; Carcinoma, Pancreatic Ductal/therapy ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic/genetics ; Gene Expression Regulation, Neoplastic/immunology ; Humans ; Immune System/cytology ; Immune System/immunology ; Immune System/metabolism ; Neoadjuvant Therapy/methods ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/immunology ; Pancreatic Neoplasms/therapy ; Reproducibility of Results ; Tumor Microenvironment/genetics ; Tumor Microenvironment/immunology
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2021-04-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.649061
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Article: Rintatolimod (Ampligen

El Haddaoui, Hassana / Brood, Rianne / Latifi, Diba / Oostvogels, Astrid A / Klaver, Yarne / Moskie, Miranda / Mustafa, Dana A / Debets, Reno / van Eijck, Casper H J

Cancers

2022 Volume 14, Issue 6

Abstract: Background: Treatment with the TLR-3 agonist rintatolimod may improve pancreatic cancer patients’ survival via immunomodulation, but the effect is unproven. Methods: In this single-center named patient program, patients with locally advanced pancreatic ... ...

Abstract	Background: Treatment with the TLR-3 agonist rintatolimod may improve pancreatic cancer patients’ survival via immunomodulation, but the effect is unproven. Methods: In this single-center named patient program, patients with locally advanced pancreatic cancer (LAPC) or metastatic disease were treated with rintatolimod (six weeks total, twice per week, with a maximum of 400 mg per infusion). The primary endpoints were the systemic immune-inflammation index (SIII), the neutrophil to lymphocyte ratio (NLR), and the absolute counts of 18 different populations of circulating immune cells as measured by flow cytometry. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Subgroup analyses were performed in long-term survivors (>1-year overall survival after starting rintatolimod) and compared to short-term survivors (≤1 year). Results: Between January 2017 and February 2019, twenty-seven patients with stable LAPC or metastatic disease were pre-treated with FOLFIRINOX and treated with rintatolimod. Rintatolimod treatment was well-tolerated. The SIII and NLR values were significantly lower in the 11 long-term survivors, versus 16 short-term survivors. The numbers of B-cells were significantly increased in long-term survivors. Numbers of T cells and myeloid cells were not significantly increased after treatment with rintatolimod. Median PFS was 13 months with rintatolimod, versus 8.6 months in a subset of matched controls (n = 27, hazard ratio = 0.52, 95% CI = 0.28−0.90, p = 0.007). The median OS was 19 months with rintatolimod, versus 12.5 months in the matched control (hazard ratio = 0.51, 95% CI = 0.28−0.90, p = 0.016). Conclusions: Treatment with rintatolimod showed a favorable effect on the numbers of peripheral B cells in patients with pancreatic cancer and improved survival in pancreatic cancer, but additional evidence is required.
Language	English
Publishing date	2022-03-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14061377
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Article ; Online: Early results after operatively versus non-operatively treated flail chest: a retrospective study focusing on outcome and complications.

Wijffels, Mathieu M E / Hagenaars, Tjebbe / Latifi, Diba / Van Lieshout, Esther M M / Verhofstad, Michael H J

European journal of trauma and emergency surgery : official publication of the European Trauma Society

2018 Volume 46, Issue 3, Page(s) 539–547

Abstract: Purpose: Flail chest was traditionally treated non-operatively using mechanical ventilation and pain control. In order to reduce the occurrence of ventilation-associated complications and long-term disability, operative rib fixation is becoming a proven ...

Abstract	Purpose: Flail chest was traditionally treated non-operatively using mechanical ventilation and pain control. In order to reduce the occurrence of ventilation-associated complications and long-term disability, operative rib fixation is becoming a proven standard therapy for these patients. However, the consequences of the surgical complications may influence success rates negatively. The aim of this study was to compare the outcome of flail chest treatment by surgical rib fixation with non-operative treatment, with special focus on the impact of surgical complications. Methods: A retrospective case series of operatively treated flail chest patients was compared with non-operatively treated patients. Patients' injury and treatment characteristics and outcome parameters (e.g., duration of mechanical ventilation, length of Intensive Care stay (ICLOS) and hospital length of stay (HLOS), mortality, surgery-related complications and pneumonia) were collected from the patients' medical files. Crude and matched-pairs analyses were performed in SPSS. Results: Twenty-three operatively and 47 non-operatively treated patients were enrolled. Operatively treated patients required significantly shorter mechanical ventilation; median 4 days versus 12 days for the non-operative group (p = 0.011). The matched-pairs analysis also showed a lower pneumonia rate (35% versus 80%; p = 0.035) and a shorter HLOS (median 21 versus 23 days; p = 0.028) in the operative group. No significant differences in duration of ICLOS, and occurrence of other injury-related adverse events were found between both groups.  Seven surgery-related complications occurred, of which three required invasive solutions. Conclusions: Operative fixation of a flail chest in trauma patients results in a lower rate of pneumonia, less mechanical ventilation days and shorter hospital stay, compared with non-operative treatment, but at the cost of surgery-related complications requiring invasive solutions in some cases.
MeSH term(s)	Adult ; Aged ; Female ; Flail Chest/surgery ; Flail Chest/therapy ; Humans ; Length of Stay/statistics & numerical data ; Male ; Matched-Pair Analysis ; Middle Aged ; Pneumonia/epidemiology ; Postoperative Complications ; Respiration, Artificial ; Retrospective Studies ; Trauma Centers
Language	English
Publishing date	2018-05-21
Publishing country	Germany
Document type	Comparative Study ; Journal Article
ZDB-ID	2275480-5
ISSN	1863-9941 ; 1863-9933
ISSN (online)	1863-9941
ISSN	1863-9933
DOI	10.1007/s00068-018-0961-4
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Zs.A 1221: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Rintatolimod Induces Antiviral Activities in Human Pancreatic Cancer Cells: Opening for an Anti-COVID-19 Opportunity in Cancer Patients?

Mustafa, Dana A M / Saida, Lawlaw / Latifi, Diba / Wismans, Leonoor V / de Koning, Willem / Zeneyedpour, Lona / Luider, Theo M / van den Hoogen, Bernadette / van Eijck, Casper H J

Cancers

2021 Volume 13, Issue 12

Abstract: Severe acute respiratory virus-2 (SARS-CoV-2) has spread globally leading to a devastating loss of life. Large registry studies have begun to shed light on the epidemiological and clinical vulnerabilities of cancer patients who succumb to or endure poor ... ...

Abstract	Severe acute respiratory virus-2 (SARS-CoV-2) has spread globally leading to a devastating loss of life. Large registry studies have begun to shed light on the epidemiological and clinical vulnerabilities of cancer patients who succumb to or endure poor outcomes of SARS-CoV-2. Specific treatment for COVID-19 infections in cancer patients is lacking while the demand for treatment is increasing. Therefore, we explored the effect of Rintatolimod (Ampligen
Language	English
Publishing date	2021-06-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13122896
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Article ; Online: Feasibility, safety, and efficacy of stereotactic body radiotherapy combined with intradermal heat-killed mycobacterium obuense (IMM-101) vaccination for non-progressive locally advanced pancreatic cancer, after induction chemotherapy with (modified)FOLFIRINOX - The LAPC-2 trial.

van 't Land, Freek R / Latifi, Diba / Moskie, Miranda / Homs, Marjolein Y V / Bosscha, Koop / Bonsing, Bert A / Mieog, Sven D / van der Harst, Erwin / Coene, Peter-Paul L O / Wijsman, Jan H / van der Schelling, George P / Groot Koerkamp, Bas / Nuyttens, Joost J / van Eijck, Casper H J

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

2023 Volume 183, Page(s) 109541

Abstract: Background and purpose: In this phase I/II trial, non-progressive locally advanced pancreatic cancer (LAPC) patients after (modified)FOLFIRINOX therapy were treated with stereotactic body radiotherapy (SBRT) combined with heat-killed mycobacterium (IMM- ... ...

Abstract	Background and purpose: In this phase I/II trial, non-progressive locally advanced pancreatic cancer (LAPC) patients after (modified)FOLFIRINOX therapy were treated with stereotactic body radiotherapy (SBRT) combined with heat-killed mycobacterium (IMM-101) vaccinations. We aimed to assess safety, feasibility, and efficacy of this treatment approach. Materials and methods: On five consecutive days, patients received a total of 40 Gray (Gy) of SBRT with a dose of 8 Gy per fraction. Starting two weeks prior to SBRT, they in addition received six bi-weekly intradermal vaccinations with one milligram of IMM-101. The primary outcomes were the number of grade 4 or higher adverse events and the one-year progression free-survival (PFS) rate. Results: Thirty-eight patients were included and started study treatment. Median follow-up was 28.4 months (95 %CI 24.3 - 32.6). We observed one grade 5, no grade 4 and thirteen grade 3 adverse events, none related to IMM-101. The one-year PFS rate was 47 %, the median PFS was 11.7 months (95 %CI 11.0 - 12.5) and the median overall survival was 19.0 months (95 %CI 16.2 - 21.9). Eight (21 %) tumors were resected, of which 6 (75 %) were R0 resections. Outcomes were comparable with the outcomes of the patients from the previous LAPC-1 trial, in which LAPC patients were treated with SBRT, without IMM-101. Conclusion: Combination treatment with IMM-101 and SBRT was safe and feasible for non-progressive locally advanced pancreatic cancer patients after (modified)FOLFIRINOX. No improvement in the progression-free survival could be demonstrated by adding IMM-101 to SBRT.
MeSH term(s)	Humans ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Feasibility Studies ; Hot Temperature ; Induction Chemotherapy ; Nontuberculous Mycobacteria ; Pancreatic Neoplasms ; Radiosurgery/adverse effects
Chemical Substances	folfirinox ; IMM-101 (IZT740JY57)
Language	English
Publishing date	2023-02-20
Publishing country	Ireland
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605646-5
ISSN	1879-0887 ; 0167-8140
ISSN (online)	1879-0887
ISSN	0167-8140
DOI	10.1016/j.radonc.2023.109541
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Article ; Online: B cell immune profiles in dysbiotic vermiform appendixes of pancreatic cancer patients.

Frontiers in immunology

2023 Volume 14, Page(s) 1230306

Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with
MeSH term(s)	Humans ; Appendix/microbiology ; Appendix/pathology ; Dysbiosis ; Pancreatic Neoplasms/pathology ; Carcinoma, Pancreatic Ductal/pathology ; HLA-G Antigens
Chemical Substances	HLA-G Antigens
Language	English
Publishing date	2023-11-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1230306
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Article ; Online: Survival Benefit Associated With Resection of Locally Advanced Pancreatic Cancer After Upfront FOLFIRINOX Versus FOLFIRINOX Only: Multicenter Propensity Score-matched Analysis.

Brada, Lilly J H / Daamen, Lois A / Magermans, Lisa G / Walma, Marieke S / Latifi, Diba / van Dam, Ronald M / de Hingh, Ignace H / Liem, Mike S L / de Meijer, Vincent E / Patijn, Gijs A / Festen, Sebastiaan / Stommel, Martijn W J / Bosscha, Koop / Polée, Marco B / Nio, Yung C / Wessels, Frank J / de Vries, Jan J J / van Lienden, Krijn P / Bruijnen, Rutger C /

Busch, Olivier R / Koerkamp, Bas Groot / van Eijck, Casper / Molenaar, Quintus I / Wilmink, Hanneke J W / van Santvoort, Hjalmar C / Besselink, Marc G

Annals of surgery

2021 Volume 274, Issue 5, Page(s) 729–735

Abstract: Objective: This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection).: Background: Because the introduction of ... ...

Abstract	Objective: This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection). Background: Because the introduction of FOLFIRINOX chemotherapy, increased resection rates in LAPC patients have been reported, with improved OS. Some studies have also reported promising OS with FOLFIRINOX-only treatment in LAPC. Multicenter studies assessing the survival benefit associated with resection of LAPC versus patients treated with FOLFIRINOX-only are lacking. Methods: Patients with non-progressive LAPC after 4 cycles of FOLFIRINOX treatment, both with and without resection, were included from a prospective multicenter cohort in 16 centers (April 2015-December 2019). Cox regression analysis identified predictors for OS. One-to-one propensity score matching (PSM) was used to obtain a matched cohort of patients with and without resection. These patients were compared for OS. Results: Overall, 293 patients with LAPC were included, of whom 89 underwent a resection. Resection was associated with improved OS (24 vs 15 months, P < 0.01), as compared to patients without resection. Before PSM, resection, Charlson Comorbidity Index, and Response Evaluation Criteria in Solid Tumors (RECIST) response were predictors for OS. After PSM, resection remained associated with improved OS [Hazard Ratio (HR) 0.344, 95% confidence interval (0.222-0.534), P < 0.01], with an OS of 24 versus 15 months, as compared to patients without resection. Resection of LAPC was associated with improved 3-year OS (31% vs 11%, P < 0.01). Conclusions: Resection of LAPC after FOLFIRINOX was associated with increased OS and 3-year survival, as compared to propensity-score matched patients treated with FOLFIRINOX-only.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Female ; Fluorouracil/therapeutic use ; Follow-Up Studies ; Humans ; Irinotecan/therapeutic use ; Leucovorin/therapeutic use ; Male ; Middle Aged ; Neoplasm Staging ; Netherlands/epidemiology ; Oxaliplatin/therapeutic use ; Pancreas/pathology ; Pancreatectomy/methods ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/mortality ; Pancreatic Neoplasms/therapy ; Propensity Score ; Prospective Studies ; Survival Rate/trends
Chemical Substances	Antineoplastic Agents ; folfirinox ; Oxaliplatin (04ZR38536J) ; Irinotecan (7673326042) ; Leucovorin (Q573I9DVLP) ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2021-07-30
Publishing country	United States
Document type	Journal Article ; Multicenter Study
ZDB-ID	340-2
ISSN	1528-1140 ; 0003-4932
ISSN (online)	1528-1140
ISSN	0003-4932
DOI	10.1097/SLA.0000000000005120
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Article ; Online: Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes.

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Article: Rintatolimod (Ampligen

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Article ; Online: Early results after operatively versus non-operatively treated flail chest: a retrospective study focusing on outcome and complications.

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Article: Rintatolimod Induces Antiviral Activities in Human Pancreatic Cancer Cells: Opening for an Anti-COVID-19 Opportunity in Cancer Patients?

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Article ; Online: Feasibility, safety, and efficacy of stereotactic body radiotherapy combined with intradermal heat-killed mycobacterium obuense (IMM-101) vaccination for non-progressive locally advanced pancreatic cancer, after induction chemotherapy with (modified)FOLFIRINOX - The LAPC-2 trial.

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Article ; Online: B cell immune profiles in dysbiotic vermiform appendixes of pancreatic cancer patients.

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Article ; Online: Survival Benefit Associated With Resection of Locally Advanced Pancreatic Cancer After Upfront FOLFIRINOX Versus FOLFIRINOX Only: Multicenter Propensity Score-matched Analysis.

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