Cancers

Research

11 pages, 1668 KiB

Open AccessArticle

Prediction of Tumor Cellularity in Resectable PDAC from Preoperative Computed Tomography Imaging

by Friederike Jungmann, Georgios A. Kaissis, Sebastian Ziegelmayer, Felix Harder, Clara Schilling, Hsi-Yu Yen, Katja Steiger, Wilko Weichert, Rebekka Schirren, Ishan Ekin Demir, Helmut Friess, Markus R. Makowski, Rickmer F. Braren and Fabian K. Lohöfer

Cancers 2021, 13(9), 2069; https://doi.org/10.3390/cancers13092069 - 25 Apr 2021

Cited by 10 | Viewed by 2364

Abstract

Background: PDAC remains a tumor entity with poor prognosis and a 5-year survival rate below 10%. Recent research has revealed invasive biomarkers, such as distinct molecular subtypes, predictive for therapy response and patient survival. Non-invasive prediction of individual patient outcome however remains an [...] Read more.

Background: PDAC remains a tumor entity with poor prognosis and a 5-year survival rate below 10%. Recent research has revealed invasive biomarkers, such as distinct molecular subtypes, predictive for therapy response and patient survival. Non-invasive prediction of individual patient outcome however remains an unresolved task. Methods: Discrete cellularity regions of PDAC resection specimen (n = 43) were analyzed by routine histopathological work up. Regional tumor cellularity and CT-derived Hounsfield Units (HU, n = 66) as well as iodine concentrations were regionally matched. One-way ANOVA and pairwise t-tests were performed to assess the relationship between different cellularity level in conventional, virtual monoenergetic 40 keV (monoE 40 keV) and iodine map reconstructions. Results: A statistically significant negative correlation between regional tumor cellularity in histopathology and CT-derived HU from corresponding image regions was identified. Radiological differentiation was best possible in monoE 40 keV CT images. However, HU values differed significantly in conventional reconstructions as well, indicating the possibility of a broad clinical application of this finding. Conclusion: In this study we establish a novel method for CT-based prediction of tumor cellularity for in-vivo tumor characterization in PDAC patients. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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11 pages, 1309 KiB

Open AccessArticle

Synergistic Analysis of Protein Corona and Haemoglobin Levels Detects Pancreatic Cancer

by Damiano Caputo, Luca Digiacomo, Chiara Cascone, Daniela Pozzi, Sara Palchetti, Riccardo Di Santo, Erica Quagliarini, Roberto Coppola, Morteza Mahmoudi and Giulio Caracciolo

Cancers 2021, 13(1), 93; https://doi.org/10.3390/cancers13010093 - 30 Dec 2020

Cited by 20 | Viewed by 2598

Abstract

Simultaneous detection of multiple analytes from a single biological sample is gaining more attention in the development of more reliable and point-of-care diagnostic devices. We developed a multiplexed strategy that combined outcomes of clinical biomarkers with analysis of the protein corona that forms [...] Read more.

Simultaneous detection of multiple analytes from a single biological sample is gaining more attention in the development of more reliable and point-of-care diagnostic devices. We developed a multiplexed strategy that combined outcomes of clinical biomarkers with analysis of the protein corona that forms around graphene oxide sheets upon exposure to patient’s plasma. As a paradigmatic case study, we selected pancreatic ductal adenocarcinoma (PDAC), mainly because of the absence of effective detection strategies that resulted in an extremely low five-year survival rate after diagnosis (<10%). Association of protein corona analysis and haemoglobin levels discriminated PDAC patients from healthy volunteers in up to 90% of cases. If further confirmed in larger-cohort studies, this approach may be used in the detection of PDAC. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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17 pages, 2252 KiB

Open AccessArticle

A Novel Four-Gene Score to Predict Pathologically Complete (R0) Resection and Survival in Pancreatic Cancer

by Masanori Oshi, Yoshihisa Tokumaru, Ankit Patel, Li Yan, Ryusei Matsuyama, Itaru Endo, Matthew H.G. Katz and Kazuaki Takabe

Cancers 2020, 12(12), 3635; https://doi.org/10.3390/cancers12123635 - 4 Dec 2020

Cited by 24 | Viewed by 2565

Abstract

Pathologically complete (R0) resection is essential for prolonged survival in pancreatic cancer. Survival depends not only on surgical technique, but also on cancer biology. A biomarker to predict survival is a critical need in pancreatic treatment. We hypothesized that this 4-gene score, which [...] Read more.

Pathologically complete (R0) resection is essential for prolonged survival in pancreatic cancer. Survival depends not only on surgical technique, but also on cancer biology. A biomarker to predict survival is a critical need in pancreatic treatment. We hypothesized that this 4-gene score, which was reported to reflect cell proliferation, is a translatable predictive biomarker for pancreatic cancer. A total of 954 pancreatic cancer patients from multiple cohorts were analyzed and validated. Pancreatic cancer had the 10th highest median score of 32 cancers in The Cancer Genome Atlas (TCGA) cohort. The four-gene score significantly correlated with pathological grade and MKI67 expression. The high four-gene score enriched cell proliferation-related and cancer aggressiveness-related gene sets. The high score was associated with activation of KRAS, p53, transforming growth factor (TGF)-β, and E2F pathways, and with high alteration rate of KRAS and CDKN2A genes. The high score was also significantly associated with reduced CD8⁺ T cell infiltration of tumors, but with high levels of interferon-γ and cytolytic activity in tumors. The four-gene score correlated with the area under the curve of irinotecan and sorafenib in primary pancreatic cancer, and with paclitaxel and doxorubicin in metastatic pancreatic cancer. The high four-gene score was associated with significantly fewer R0 resections and worse survival. The novelty of the study is in the application of the four-gene score to pancreatic cancer, rather than the bioinformatics technique itself. Future analyses of inoperable lesions are expected to clarify the utility of our score as a predictive biomarker of systemic treatments. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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18 pages, 5631 KiB

Open AccessArticle

Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing

by Manoj Amrutkar, Nils Tore Vethe, Caroline S. Verbeke, Monica Aasrum, Anette Vefferstad Finstadsveen, Petra Sántha and Ivar P. Gladhaug

Cancers 2020, 12(12), 3628; https://doi.org/10.3390/cancers12123628 - 3 Dec 2020

Cited by 17 | Viewed by 3557

Abstract

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and [...] Read more.

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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18 pages, 7355 KiB

Open AccessArticle

Lactobacillus Attenuate the Progression of Pancreatic Cancer Promoted by Porphyromonas Gingivalis in K-ras^G12D Transgenic Mice

by Shan-Ming Chen, Li-Jin Hsu, Hsiang-Lin Lee, Ching-Pin Lin, Szu-Wei Huang, Caucasus Jun-Lin Lai, Chia-Wei Lin, Wan-Ting Chen, Yu-Jen Chen, Yu-Chien Lin, Chi-Chieh Yang and Ming-Shiou Jan

Cancers 2020, 12(12), 3522; https://doi.org/10.3390/cancers12123522 - 26 Nov 2020

Cited by 30 | Viewed by 4635

Abstract

Accumulating evidence suggests that there is a link between the host microbiome and pancreatic carcinogenesis, and that Porphyromonas gingivalis (P. gingivalis) increases the risk of developing pancreatic cancer. The aim of the current study was to clarify the role of P. gingivalis in [...] Read more.

Accumulating evidence suggests that there is a link between the host microbiome and pancreatic carcinogenesis, and that Porphyromonas gingivalis (P. gingivalis) increases the risk of developing pancreatic cancer. The aim of the current study was to clarify the role of P. gingivalis in the pathogenesis of pancreatic cancer and the potential immune modulatory effects of probiotics. The six-week-old LSL-K-rasG12D; Pdx-1-cre (KC) mice smeared P. gingivalis on the gums, causing pancreatic intraepithelial neoplasia (PanIN) after four weeks to be similar to the extent of lesions in untreated KC mice at 24 weeks. The oral inoculation of P. gingivalis of six-week-old LSL-K-ras^G12D; Pdx-1-cre (KC) mice caused significantly pancreatic intraepithelial neoplasia (PanIN) after treatment four weeks is similar to the extent of lesions in untreated KC mice at 24 weeks. The pancreas weights of P. gingivalis plus probiotic-treated mice were significantly lower than the mice treated with P. gingivalis alone (P = 0.0028). The histological expressions of Snail-1, ZEB-1, collagen fibers, Galectin-3, and PD-L1 staining in the pancreas were also notably lower. In addition, probiotic administration reduced the histological expression of Smad3 and phosphorylated Smad3 in P. gingivalis treated KC mice. We demonstrated that oral exposure to P. gingivalis can accelerate the development of PanIN lesions. Probiotics are likely to have a beneficial effect by reducing cancer cell proliferation and viability, inhibiting PanIN progression, and cancer cell metastasis (Epithelial–mesenchymal transition, EMT). The transforming growth factor-β signaling pathway may be involved in the tumor suppressive effects of probiotics. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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Review

Jump to: Research, Other

41 pages, 3382 KiB

Open AccessReview

Pancreatic Cancer and Immunotherapy: A Clinical Overview

by Florentine E. F. Timmer, Bart Geboers, Sanne Nieuwenhuizen, Madelon Dijkstra, Evelien A. C. Schouten, Robbert S. Puijk, Jan J. J. de Vries, M. Petrousjka van den Tol, Anna M. E. Bruynzeel, Mirte M. Streppel, Johanna W. Wilmink, Hans J. van der Vliet, Martijn R. Meijerink, Hester J. Scheffer and Tanja D. de Gruijl

Cancers 2021, 13(16), 4138; https://doi.org/10.3390/cancers13164138 - 17 Aug 2021

Cited by 47 | Viewed by 6474

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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12 pages, 922 KiB

Open AccessReview

Ablation in Pancreatic Cancer: Past, Present and Future

by Govindarajan Narayanan, Dania Daye, Nicole M. Wilson, Raihan Noman, Ashwin M. Mahendra and Mehul H. Doshi

Cancers 2021, 13(11), 2511; https://doi.org/10.3390/cancers13112511 - 21 May 2021

Cited by 12 | Viewed by 3025

Abstract

The insidious onset and aggressive nature of pancreatic cancer contributes to the poor treatment response and high mortality of this devastating disease. While surgery, chemotherapy and radiation have contributed to improvements in overall survival, roughly 90% of those afflicted by this disease will [...] Read more.

The insidious onset and aggressive nature of pancreatic cancer contributes to the poor treatment response and high mortality of this devastating disease. While surgery, chemotherapy and radiation have contributed to improvements in overall survival, roughly 90% of those afflicted by this disease will die within 5 years of diagnosis. The developed ablative locoregional treatment modalities have demonstrated promise in terms of overall survival and quality of life. In this review, we discuss some of the recent studies demonstrating the safety and efficacy of ablative treatments in patients with locally advanced pancreatic cancer. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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Other

Jump to: Research, Review

28 pages, 1179 KiB

Open AccessSystematic Review

Locoregional Treatment of Metastatic Pancreatic Cancer Utilizing Resection, Ablation and Embolization: A Systematic Review

by Florentine E. F. Timmer, Bart Geboers, Sanne Nieuwenhuizen, Evelien A. C. Schouten, Madelon Dijkstra, Jan J. J. de Vries, M. Petrousjka van den Tol, Martijn R. Meijerink and Hester J. Scheffer

Cancers 2021, 13(7), 1608; https://doi.org/10.3390/cancers13071608 - 31 Mar 2021

Cited by 13 | Viewed by 2924

Abstract

The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains universally poor, requiring new and innovative treatment approaches. In a subset of oligometastatic PDAC patients, locoregional therapy, in addition to systemic chemotherapy, may improve survival. The aim of this systematic review was to explore [...] Read more.

The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains universally poor, requiring new and innovative treatment approaches. In a subset of oligometastatic PDAC patients, locoregional therapy, in addition to systemic chemotherapy, may improve survival. The aim of this systematic review was to explore and evaluate the current evidence on locoregional treatments for mPDAC. A systematic literature search was conducted on locoregional techniques, including resection, ablation and embolization, for mPDAC with a focus on hepatic and pulmonary metastases. A total of 59 studies were identified, including 63,453 patients. Although subject to significant bias, radical-intent local therapy for both the primary and metastatic sites was associated with a superior median overall survival from metastatic diagnosis or treatment (hepatic mPDAC 7.8–19 months; pulmonary mPDAC 22.8–47 months) compared to control groups receiving chemotherapy or best supportive care (hepatic mPDAC 4.3–7.6 months; pulmonary mPDAC 11.8 months). To recruit patients that may benefit from these local treatments, selection appears essential. Most significant is the upfront possibility of local radical pancreatic and metastatic treatment. In addition, a patient’s response to neoadjuvant systemic chemotherapy, performance status, metastatic disease load and, to a lesser degree, histological differentiation grade and tumor marker CA19-9 serum levels, are powerful prognostic factors that help identify eligible subjects. Although the exact additive value of locoregional treatments for mPDAC patients cannot be distillated from the results, locoregional primary pancreatic and metastatic treatment seems beneficial for a highly selected group of oligometastatic PDAC patients. For definite recommendations, well-designed prospective randomized controlled trials with strict in- and exclusion criteria are needed to validate these results. Full article

(This article belongs to the Special Issue New Insights into Pancreatic Cancer)

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