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14 pages, 2090 KiB

Open AccessEditor’s ChoiceArticle

Rintatolimod (Ampligen^®) Enhances Numbers of Peripheral B Cells and Is Associated with Longer Survival in Patients with Locally Advanced and Metastasized Pancreatic Cancer Pre-Treated with FOLFIRINOX: A Single-Center Named Patient Program

by Hassana el Haddaoui, Rianne Brood, Diba Latifi, Astrid A. Oostvogels, Yarne Klaver, Miranda Moskie, Dana A. Mustafa, Reno Debets and Casper H. J. van Eijck

Cancers 2022, 14(6), 1377; https://doi.org/10.3390/cancers14061377 - 08 Mar 2022

Cited by 4 | Viewed by 5358

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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22 pages, 2381 KiB

Open AccessArticle

Pancreatic Cancer Organoids in the Field of Precision Medicine: A Review of Literature and Experience on Drug Sensitivity Testing with Multiple Readouts and Synergy Scoring

by Lotta Mäkinen, Markus Vähä-Koskela, Matilda Juusola, Harri Mustonen, Krister Wennerberg, Jaana Hagström, Pauli Puolakkainen and Hanna Seppänen

Cancers 2022, 14(3), 525; https://doi.org/10.3390/cancers14030525 - 21 Jan 2022

Cited by 6 | Viewed by 3562

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a silent killer, often diagnosed late. However, it is also dishearteningly resistant to nearly all forms of treatment. New therapies are urgently needed, and with the advent of organoid culture for pancreatic cancer, an increasing number of innovative approaches are being tested. Organoids can be derived within a short enough time window to allow testing of several anticancer agents, which opens up the possibility for functional precision medicine for pancreatic cancer. At the same time, organoid model systems are being refined to better mimic the cancer, for example, by incorporation of components of the tumor microenvironment. We review some of the latest developments in pancreatic cancer organoid research and in novel treatment design. We also summarize our own current experiences with pancreatic cancer organoid drug sensitivity and resistance testing (DSRT) in 14 organoids from 11 PDAC patients. Our data show that it may be necessary to include a cell death read-out in ex vivo DSRT assays, as metabolic viability quantitation does not capture actual organoid killing. We also successfully adapted the organoid platform for drug combination synergy discovery. Lastly, live organoid culture 3D confocal microscopy can help identify individual surviving tumor cells escaping cell death even during harsh combination treatments. Taken together, the organoid technology allows the development of novel precision medicine approaches for PDAC, which paves the way for clinical trials and much needed new treatment options for pancreatic cancer patients. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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15 pages, 5567 KiB

Open AccessArticle

An Immunohistochemical Evaluation of Tumor-Associated Glycans and Mucins as Targets for Molecular Imaging of Pancreatic Ductal Adenocarcinoma

by Ruben D. Houvast, Kira Thijse, Jesse V. Groen, JiaXin Chua, Mireille Vankemmelbeke, Lindy G. Durrant, J. Sven D. Mieog, Bert A. Bonsing, Alexander L. Vahrmeijer, Peter J. K. Kuppen, A. Stijn L. P. Crobach and Cornelis F. M. Sier

Cancers 2021, 13(22), 5777; https://doi.org/10.3390/cancers13225777 - 18 Nov 2021

Cited by 3 | Viewed by 2442

Abstract

Targeted molecular imaging may overcome current challenges in the preoperative and intraoperative delineation of pancreatic ductal adenocarcinoma (PDAC). Tumor-associated glycans Le^a/c/x, sdi-Le^a, sLe^a, sLe^x, sTn as well as mucin-1 (MUC1) and mucin-5AC (MU5AC) have gained [...] Read more.

Targeted molecular imaging may overcome current challenges in the preoperative and intraoperative delineation of pancreatic ductal adenocarcinoma (PDAC). Tumor-associated glycans Le^a/c/x, sdi-Le^a, sLe^a, sLe^x, sTn as well as mucin-1 (MUC1) and mucin-5AC (MU5AC) have gained significant interest as targets for PDAC imaging. To evaluate their PDAC molecular imaging potential, biomarker expression was determined using immunohistochemistry on PDAC, (surrounding) chronic pancreatitis (CP), healthy pancreatic, duodenum, positive (LN⁺) and negative lymph node (LN⁻) tissues, and quantified using a semi-automated digital image analysis workflow. Positive expression on PDAC tissues was found on 83% for Le^a/c/x, 94% for sdi-Le^a, 98% for sLe^a, 90% for sLe^x, 88% for sTn, 96% for MUC1 and 67% for MUC5AC, where all were not affected by the application of neoadjuvant therapy. Compared to PDAC, all biomarkers were significantly lower expressed on CP, healthy pancreatic and duodenal tissues, except for sTn and MUC1, which showed a strong expression on duodenum (sTn tumor:duodenum ratio: 0.6, p < 0.0001) and healthy pancreatic tissues (MUC1 tumor:pancreas ratio: 1.0, p > 0.9999), respectively. All biomarkers are suitable targets for correct identification of LN⁺, as well as the distinction of LN⁺ from LN⁻ tissues. To conclude, this study paves the way for the development and evaluation of Le^a/c/x-, sdi-Le^a-, sLe^a-, sLe^x- and MUC5AC-specific tracers for molecular imaging of PDAC imaging and their subsequent introduction into the clinic. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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11 pages, 30335 KiB

Open AccessArticle

Artificial Intelligence-Based Segmentation of Residual Tumor in Histopathology of Pancreatic Cancer after Neoadjuvant Treatment

by Boris V. Janssen, Rutger Theijse, Stijn van Roessel, Rik de Ruiter, Antonie Berkel, Joost Huiskens, Olivier R. Busch, Johanna W. Wilmink, Geert Kazemier, Pieter Valkema, Arantza Farina, Joanne Verheij, Onno J. de Boer and Marc G. Besselink

Cancers 2021, 13(20), 5089; https://doi.org/10.3390/cancers13205089 - 12 Oct 2021

Cited by 14 | Viewed by 2929

Abstract

Background: Histologic examination of resected pancreatic cancer after neoadjuvant therapy (NAT) is used to assess the effect of NAT and may guide the choice for adjuvant treatment. However, evaluating residual tumor burden in pancreatic cancer is challenging given tumor response heterogeneity and challenging [...] Read more.

Background: Histologic examination of resected pancreatic cancer after neoadjuvant therapy (NAT) is used to assess the effect of NAT and may guide the choice for adjuvant treatment. However, evaluating residual tumor burden in pancreatic cancer is challenging given tumor response heterogeneity and challenging histomorphology. Artificial intelligence techniques may offer a more reproducible approach. Methods: From 64 patients, one H&E-stained slide of resected pancreatic cancer after NAT was digitized. Three separate classes were manually outlined in each slide (i.e., tumor, normal ducts, and remaining epithelium). Corresponding segmentation masks and patches were generated and distributed over training, validation, and test sets. Modified U-nets with varying encoders were trained, and F1 scores were obtained to express segmentation accuracy. Results: The highest mean segmentation accuracy was obtained using modified U-nets with a DenseNet161 encoder. Tumor tissue was segmented with a high mean F1 score of 0.86, while the overall multiclass average F1 score was 0.82. Conclusions: This study shows that artificial intelligence-based assessment of residual tumor burden is feasible given the promising obtained F1 scores for tumor segmentation. This model could be developed into a tool for the objective evaluation of the response to NAT and may potentially guide the choice for adjuvant treatment. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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21 pages, 4934 KiB

Open AccessArticle

Nucleolin Aptamer N6L Reprograms the Translational Machinery and Acts Synergistically with mTORi to Inhibit Pancreatic Cancer Proliferation

by Mounira Chalabi-Dchar, Elisabeth Cruz, Hichem C. Mertani, Jean-Jacques Diaz, José Courty, Ilaria Cascone and Philippe Bouvet

Cancers 2021, 13(19), 4957; https://doi.org/10.3390/cancers13194957 - 01 Oct 2021

Cited by 3 | Viewed by 2350

Abstract

We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either [...] Read more.

We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5′TOP motif in many of these mRNAs and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway, which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines, including patient-derived xenografts and tumor-derived organoids, was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation, which then undergoes translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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26 pages, 55545 KiB

Open AccessArticle

Alpha-Lipoic Acid Prevents Side Effects of Therapeutic Nanosilver without Compromising Cytotoxicity in Experimental Pancreatic Cancer

by Xuefeng An, Li Liu, Michael Schaefer, Bin Yan, Christian Scholz, Stefan Hillmer, Kangtao Wang, Yiqiao Luo, Huihui Ji, Jury Gladkich and Ingrid Herr

Cancers 2021, 13(19), 4770; https://doi.org/10.3390/cancers13194770 - 24 Sep 2021

Cited by 5 | Viewed by 3119

Abstract

Silver nanoparticles (AgNPs) have attracted attention in cancer therapy and might support the treatment of pancreatic ductal adenocarcinoma (PDAC). Silver is in clinical use in wound dressings, catheters, stents and implants. However, the side effects of systemic AgNP treatment due to silver accumulation [...] Read more.

Silver nanoparticles (AgNPs) have attracted attention in cancer therapy and might support the treatment of pancreatic ductal adenocarcinoma (PDAC). Silver is in clinical use in wound dressings, catheters, stents and implants. However, the side effects of systemic AgNP treatment due to silver accumulation limit its therapeutic application. We evaluated whether the antioxidant and natural agent α-lipoic acid might prevent these side effects. We synthesized AgNPs using an Ionic-Pulser^® Pro silver generator and determined the concentration by inductively coupled plasma–optical emission spectrometry. The effect of α-lipoic acid was examined in four PDAC and two nonmalignant cell lines by MTT, FACS analysis, TEM, xenotransplantation and immunohistochemistry. The viability of PDAC cells was nearly totally abolished by AgNP treatment, whereas nonmalignant cells largely resisted. α-Lipoic acid prevented AgNP-induced cytotoxicity in nonmalignant cells but not in PDAC cells, which might be due to the higher sensitivity of malignant cells to silver-induced cytotoxicity. α-Lipoic acid protected mitochondria from AgNP-induced damage and led to precipitation of AgNPs. AgNPs reduced the growth of tumor xenografts, and cotreatment with α-lipoic acid protected chick embryos from AgNP-induced liver damage. Together, α-lipoic acid strongly reduced AgNP-induced side effects without weakening the therapeutic efficacy. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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26 pages, 12605 KiB

Open AccessArticle

Effective Oncoleaking Treatment of Pancreatic Cancer by Claudin-Targeted Suicide Gene Therapy with Clostridium perfringens Enterotoxin (CPE)

by Jessica Pahle, Dennis Kobelt, Jutta Aumann, Diana Behrens, Ole Daberkow, Margarita Mokritzkij, Jörg Piontek, Ulrike Stein and Wolfgang Walther

Cancers 2021, 13(17), 4393; https://doi.org/10.3390/cancers13174393 - 31 Aug 2021

Cited by 6 | Viewed by 2724

Abstract

Pancreatic cancer (PC) is one of the most lethal cancers worldwide, associated with poor prognosis and restricted therapeutic options. Clostridium perfringens enterotoxin (CPE), is a pore-forming (oncoleaking) toxin, which binds to claudin-3 and -4 (Cldn3/4) causing selective cytotoxicity. Cldn3/4 are highly upregulated in [...] Read more.

Pancreatic cancer (PC) is one of the most lethal cancers worldwide, associated with poor prognosis and restricted therapeutic options. Clostridium perfringens enterotoxin (CPE), is a pore-forming (oncoleaking) toxin, which binds to claudin-3 and -4 (Cldn3/4) causing selective cytotoxicity. Cldn3/4 are highly upregulated in PC and represent an effective target for oncoleaking therapy. We utilized a translation-optimized CPE vector (optCPE) for new suicide approach of PC in vitro and in cell lines (CDX) and patient-derived pancreatic cancer xenografts (PDX) in vivo. The study demonstrates selective toxicity in Cldn3/4 overexpressing PC cells by optCPE gene transfer, mediated by pore formation, activation of apoptotic/necrotic signaling in vitro, induction of necrosis and of bystander tumor cell killing in vivo. The optCPE non-viral intratumoral in vivo jet-injection gene therapy shows targeted antitumoral efficacy in different CDX and PDX PC models, leading to reduced tumor viability and induction of tumor necrosis, which is further enhanced if combined with chemotherapy. This selective oncoleaking suicide gene therapy improves therapeutic efficacy in pancreas carcinoma and will be of value for better local control, particularly of unresectable or therapy refractory PC. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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15 pages, 2988 KiB

Open AccessArticle

The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer

by Aubrey L. Miller, Patrick L. Garcia, Samuel C. Fehling, Tracy L. Gamblin, Rebecca B. Vance, Leona N. Council, Dongquan Chen, Eddy S. Yang, Robert C. A. M. van Waardenburg and Karina J. Yoon

Cancers 2021, 13(14), 3470; https://doi.org/10.3390/cancers13143470 - 11 Jul 2021

Cited by 16 | Viewed by 3473

Abstract

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based [...] Read more.

Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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11 pages, 559 KiB

Open AccessArticle

Usefulness of Imaging Response Assessment after Irreversible Electroporation of Localized Pancreatic Cancer—Results from a Prospective Cohort

by Rasmus V. Flak, Rune V. Fisker, Niels H. Bruun, Mogens T. Stender, Ole Thorlacius-Ussing and Lars J. Petersen

Cancers 2021, 13(12), 2862; https://doi.org/10.3390/cancers13122862 - 08 Jun 2021

Cited by 2 | Viewed by 1828

Abstract

(1) Background: Irreversible electroporation (IRE) is a nonthermal ablation technique that is being studied in nonmetastatic pancreatic cancer (PC). Most published studies use imaging outcomes as an efficacy endpoint, but imaging interpretation can be difficult and has yet to be correlated with survival. [...] Read more.

(1) Background: Irreversible electroporation (IRE) is a nonthermal ablation technique that is being studied in nonmetastatic pancreatic cancer (PC). Most published studies use imaging outcomes as an efficacy endpoint, but imaging interpretation can be difficult and has yet to be correlated with survival. The aim of this study was to examine the correlation of imaging endpoints with survival in a cohort of IRE-treated PC patients. (2) Methods: Several imaging endpoints were examined before and after IRE on ¹⁸F-fluorodeoxyglucose positron emission tomography (PET) with computed tomography. Separate analyses were performed at the patient and lesion levels. Mortality rate (MR) ratios for imaging endpoints after IRE were estimated. (3) Results: Forty-one patients were included. Patient-level analysis revealed that progressive disease (PD), as defined by RECIST 1.1, is correlated with a higher MR at all time intervals, but PD, as defined by EORTC PET response criteria, is only correlated with the MR in the longest interval. No correlation was found between PD, as defined by RECIST, and the MR in the lesion-level analysis. (4) Conclusions: Patient-level PD, as defined by RECIST, was correlated with poorer survival after IRE ablation, whereas no correlations were observed in the lesion-level analyses. Several promising lesion-level outcomes were identified. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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12 pages, 718 KiB

Open AccessArticle

Gemcitabine/Nab-Paclitaxel versus FOLFIRINOX in Locally Advanced Pancreatic Cancer: A European Multicenter Study

by Nicolas Williet, Angelica Petrillo, Gaël Roth, Michele Ghidini, Mila Petrova, Julien Forestier, Anthony Lopez, Audrey Thoor, Lucie Weislinger, Ferdinando De Vita, Julien Taieb and Jean Marc Phelip

Cancers 2021, 13(11), 2797; https://doi.org/10.3390/cancers13112797 - 04 Jun 2021

Cited by 13 | Viewed by 3208

Abstract

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with [...] Read more.

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with either GN or FFX as the first-line therapy between 2010 and 2019. Coprimary objectives were progression-free survival (PFS) and overall survival (OS), both estimated using the Kaplan–Meier method. Results: A total of 147 patients (GN: n = 60; FFX: n = 87) were included. Tumor resection rates were similar between the two groups (16.7% vs. 16.1%; p = 1), with similar R0 resection rates (88.9%). Median PFS rates were not statistically different: 9 months (95% CI: 8–13.5) vs. 12.1 months (95% CI: 10.1–14.6; p = 0.8), respectively. Median OS rates were 15.7 months (95% CI: 12.6–20.2) and 16.7 months (95% CI: 14.8–20.4; p = 0.7), respectively. Abdominal pain at the baseline (HR = 2.03, p = 0.03), tumors located in the tail of the pancreas (HR = 4.35, p = 0.01), CA19-9 > 200 UI/L (HR = 2.03, p = 0.004) and tumor resection (HR = 0.37, p = 0.007) were independent prognostic factors for PFS, similarly to OS. CA19-9 ≤ 200 UI/L (OR = 2.6, p = 0.047) was predictive of the tumor response. Consolidation chemoradiotherapy, more often used in the FFX group (11.7% vs. 50.6%; p < 0.001), was not predictive. Conclusion: This retrospective study did not show any difference between GN and FFX as the first-line treatment in patients with LAPC. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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Review

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17 pages, 341 KiB

Open AccessReview

Orchestrating Treatment Modalities in Metastatic Pancreatic Neuroendocrine Tumors—Need for a Conductor

by Alexander R. Siebenhüner, Melanie Langheinrich, Juliane Friemel, Niklaus Schäfer, Dilmurodjon Eshmuminov and Kuno Lehmann

Cancers 2022, 14(6), 1478; https://doi.org/10.3390/cancers14061478 - 14 Mar 2022

Cited by 3 | Viewed by 1936

Abstract

Pancreatic neuroendocrine tumors (pNETs) are a vast growing disease. Over 50% of these tumors are recognized at advanced stages with lymph node, liver, or distant metastasis. An ongoing controversy is the role of surgery in the metastatic setting as dedicated systemic treatments have [...] Read more.

Pancreatic neuroendocrine tumors (pNETs) are a vast growing disease. Over 50% of these tumors are recognized at advanced stages with lymph node, liver, or distant metastasis. An ongoing controversy is the role of surgery in the metastatic setting as dedicated systemic treatments have emerged recently and shown benefits in randomized trials. Today, liver surgery is an option for advanced pNETs if the tumor has a favorable prognosis, reflected by a low to moderate proliferation index (G1 and G2). Surgery in this well-selected population may prolong progression-free and overall survival. Optimal selection of a treatment plan for an individual patient should be considered in a multidisciplinary tumor board. However, while current guidelines offer a variety of modalities, there is so far only a limited focus on the right timing. Available data is based on small case series or retrospective analyses. The focus of this review is to highlight the right time-point for surgery in the setting of the multimodal treatment of an advanced pancreatic neuroendocrine tumor. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

46 pages, 1071 KiB

Open AccessReview

Overview and Future Perspectives on Tumor-Targeted Positron Emission Tomography and Fluorescence Imaging of Pancreatic Cancer in the Era of Neoadjuvant Therapy

by Martijn A. van Dam, Floris A. Vuijk, Judith A. Stibbe, Ruben D. Houvast, Saskia A. C. Luelmo, Stijn Crobach, Shirin Shahbazi Feshtali, Lioe-Fee de Geus-Oei, Bert A. Bonsing, Cornelis F. M. Sier, Peter J. K. Kuppen, Rutger-Jan Swijnenburg, Albert D. Windhorst, Jacobus Burggraaf, Alexander L. Vahrmeijer and J. Sven D. Mieog

Cancers 2021, 13(23), 6088; https://doi.org/10.3390/cancers13236088 - 02 Dec 2021

Cited by 9 | Viewed by 3735

Abstract

Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally [...] Read more.

Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally advanced disease. Neoadjuvant therapy aims to improve radical resection rates by reducing tumor mass and (partial) encasement of important vascular structures, as well as eradicating occult micrometastases. Results from recent multicenter clinical trials evaluating this approach demonstrate prolonged survival and increased complete surgical resection rates (R0). Currently, tumor response to neoadjuvant therapy is monitored using computed tomography (CT) following the RECIST 1.1 criteria. Accurate assessment of neoadjuvant treatment response and tumor resectability is considered a major challenge, as current conventional imaging modalities provide limited accuracy and specificity for discrimination between necrosis, fibrosis, and remaining vital tumor tissue. As a consequence, resections with tumor-positive margins and subsequent early locoregional tumor recurrences are observed in a substantial number of patients following surgical resection with curative intent. Of these patients, up to 80% are diagnosed with recurrent disease after a median disease-free interval of merely 8 months. These numbers underline the urgent need to improve imaging modalities for more accurate assessment of therapy response and subsequent re-staging of disease, thereby aiming to optimize individual patient’s treatment strategy. In cases of curative intent resection, additional intra-operative real-time guidance could aid surgeons during complex procedures and potentially reduce the rate of incomplete resections and early (locoregional) tumor recurrences. In recent years intraoperative imaging in cancer has made a shift towards tumor-specific molecular targeting. Several important molecular targets have been identified that show overexpression in PDAC, for example: CA19.9, CEA, EGFR, VEGFR/VEGF-A, uPA/uPAR, and various integrins. Tumor-targeted PET/CT combined with intraoperative fluorescence imaging, could provide valuable information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. Methods: A literature search in the PubMed database and (inter)national trial registers was conducted, focusing on studies published over the last 15 years. Data and information of eligible articles regarding PET/CT as well as fluorescence imaging in PDAC were reviewed. Areas covered: This review covers the current strategies, obstacles, challenges, and developments in targeted tumor imaging, focusing on the feasibility and value of PET/CT and fluorescence imaging for integration in the work-up and treatment of PDAC. An overview is given of identified targets and their characteristics, as well as the available literature of conducted and ongoing clinical and preclinical trials evaluating PDAC-targeted nuclear and fluorescent tracers. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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15 pages, 734 KiB

Open AccessReview

The Potential of Induced Pluripotent Stem Cells to Advance the Treatment of Pancreatic Ductal Adenocarcinoma

by Ricki T. Krog, Noel F. C. C. de Miranda, Alexander L. Vahrmeijer and Nigel G. Kooreman

Cancers 2021, 13(22), 5789; https://doi.org/10.3390/cancers13225789 - 18 Nov 2021

Cited by 2 | Viewed by 3043

Abstract

Advances in the treatment of pancreatic ductal adenocarcinoma (PDAC) using neoadjuvant chemoradiotherapy, chemotherapy, and immunotherapy have had minimal impact on the overall survival of patients. A general lack of immunogenic features and a complex tumor microenvironment (TME) are likely culprits for therapy refractoriness [...] Read more.

Advances in the treatment of pancreatic ductal adenocarcinoma (PDAC) using neoadjuvant chemoradiotherapy, chemotherapy, and immunotherapy have had minimal impact on the overall survival of patients. A general lack of immunogenic features and a complex tumor microenvironment (TME) are likely culprits for therapy refractoriness in PDAC. Induced pluripotent stem cells (iPSCs) should be explored as a means to advance the treatment options for PDAC, by providing representative in vitro models of pancreatic cancer development. In addition, iPSCs could be used for tailor-made cellular immunotherapies or as a source of tumor-associated antigens in the context of vaccination. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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19 pages, 341 KiB

Open AccessReview

Neoadjuvant Treatment Strategies in Resectable Pancreatic Cancer

by Aurélien Lambert, Lilian Schwarz, Michel Ducreux and Thierry Conroy

Cancers 2021, 13(18), 4724; https://doi.org/10.3390/cancers13184724 - 21 Sep 2021

Cited by 18 | Viewed by 2283

Abstract

Complete surgical resection is the cornerstone of curative therapy for resectable pancreatic adenocarcinoma. Upfront surgery is the gold standard, but it is rarely curative. Neoadjuvant treatment is a logical option, as it may overcome some of the limitations of adjuvant therapy and has [...] Read more.

Complete surgical resection is the cornerstone of curative therapy for resectable pancreatic adenocarcinoma. Upfront surgery is the gold standard, but it is rarely curative. Neoadjuvant treatment is a logical option, as it may overcome some of the limitations of adjuvant therapy and has already shown some encouraging results. The main concern regarding neoadjuvant therapy is the risk of disease progression during chemotherapy, meaning the opportunity to undergo the intended curative surgery is missed. We reviewed all recent literature in the following areas: major surveys, retrospective studies, meta-analyses, and randomized trials. We then selected the ongoing trials that we believe are of interest in this field and report here the results of a comprehensive review of the literature. Meta-analyses and randomized trials suggest that neoadjuvant treatment has a positive effect. However, no study to date can be considered practice changing. We considered design, endpoints, inclusion criteria and results of available randomized trials. Neoadjuvant treatment appears to be at least a feasible strategy for patients with resectable pancreatic cancer. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

22 pages, 1175 KiB

Open AccessReview

Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC

by Philip Dujardin, Anna K. Baginska, Sebastian Urban and Barbara M. Grüner

Cancers 2021, 13(16), 4187; https://doi.org/10.3390/cancers13164187 - 20 Aug 2021

Cited by 5 | Viewed by 3328

Abstract

Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, [...] Read more.

Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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Open AccessFeature PaperReview

The Microbiome as a Potential Target for Therapeutic Manipulation in Pancreatic Cancer

by Rozana Abdul Rahman, Angela Lamarca, Richard A. Hubner, Juan W. Valle and Mairéad G. McNamara

Cancers 2021, 13(15), 3779; https://doi.org/10.3390/cancers13153779 - 27 Jul 2021

Cited by 17 | Viewed by 6115

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the second most common cause of cancer-related death by 2030, with an overall 5-year survival rate between 7% and 9%. Despite recent advances in surgical, chemotherapy, and [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the second most common cause of cancer-related death by 2030, with an overall 5-year survival rate between 7% and 9%. Despite recent advances in surgical, chemotherapy, and radiotherapy techniques, the outcome for patients with PDAC remains poor. Poor prognosis is multifactorial, including the likelihood of sub-clinical metastatic disease at presentation, late-stage at presentation, absence of early and reliable diagnostic biomarkers, and complex biology surrounding the extensive desmoplastic PDAC tumour micro-environment. Microbiota refers to all the microorganisms found in an environment, whereas microbiome is the collection of microbiota and their genome within an environment. These organisms reside on body surfaces and within mucosal layers, but are most abundantly found within the gut. The commensal microbiome resides in symbiosis in healthy individuals and contributes to nutritive, metabolic and immune-modulation to maintain normal health. Dysbiosis is the perturbation of the microbiome that can lead to a diseased state, including inflammatory bowel conditions and aetiology of cancer, such as colorectal and PDAC. Microbes have been linked to approximately 10% to 20% of human cancers, and they can induce carcinogenesis by affecting a number of the cancer hallmarks, such as promoting inflammation, avoiding immune destruction, and microbial metabolites can deregulate host genome stability preceding cancer development. Significant advances have been made in cancer treatment since the advent of immunotherapy. The microbiome signature has been linked to response to immunotherapy and survival in many solid tumours. However, progress with immunotherapy in PDAC has been challenging. Therefore, this review will focus on the available published evidence of the microbiome association with PDAC and explore its potential as a target for therapeutic manipulation. Full article

(This article belongs to the Special Issue Combination and Innovative Therapies for Pancreatic Cancer)

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