Pancreatic Cancer Treatment: Surgery, Chemotherapy, Chemoradiation, and Upcoming Trends

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 May 2023) | Viewed by 37324

Special Issue Editors

Center of Surgery, Faculty of Medicine, Department of General and Visceral Surgery, Medical Center – University of Freiburg, 79085 Freiburg im Breisgau, Germany
Center of Surgery, Faculty of Medicine, Department of General and Visceral Surgery, Medical Center – University of Freiburg, 79085 Freiburg im Breisgau, Germany
Interests: Pancreatic cancer; oncogenic signaling; tumor metabolism; tumor microenvironment; immunotherapy; pancreatic surgery
Center of Surgery, Faculty of Medicine, Department of General and Visceral Surgery, Medical Center – University of Freiburg, 79085 Freiburg im Breisgau, Germany

Special Issue Information

Dear Colleagues,

Receiving a diagnosis of pancreatic cancer remains gravely menacing and is still tied to a dire prognosis. In spite of substantial progress in the molecular understanding of this tumor entity on different levels, including genetics and epigenetics, transcriptomics, oncogenic signaling, tumor metabolism, and tumor microenvironment, successful clinical translation and, thus, benefits to patients have been marginal. Yet, recent clinical developments have led to some improvements in patient outlook, and the landscape of therapeutic strategies for pancreatic cancer is evolving. The introduction of (m)FOLFIRINOX combination chemotherapy has not only opened new avenues in palliative and adjuvant settings, but also demonstrates remarkable neoadjuvant potency, enabling the downsizing and resection of locally advanced tumors, altering surgical strategies in the process. Furthermore, a first meaningful targeted therapy concept has been established with PARP inhibition as a maintenance therapy after first-line platinum-based chemotherapy for a small subgroup of patients with germline BRCA mutations.

The continuous improvement of interdisciplinary care within multimodal therapeutic concepts and the implementation of personalized treatment approaches harnessing molecular insights will, however, be required for further substantial progress and meaningful impact on patients’ lives and prognosis. As an example, the organoid-based, pharmacogenetically instructed stratification of induction, adjuvant, or palliative therapy concepts is currently being explored. Furthermore, the value of radiotherapy in neoadjuvant, intraoperative, and local recurrence settings awaits clarification.

This Special Issue aims to provide a platform for the communication of preclinical and clinical advancements in the form of primary data and review summaries. It will focus on basic, translational, and clinical developments, highlighting interdisciplinary approaches, including neoadjuvant and adjuvant chemotherapy, (neo-) adjuvant and intraoperative radio- (chemo-) therapy, and targeted and immunotherapy, as well as upcoming trends in treatment for pancreatic cancer.

Prof. Dr. Markus K. Diener
Dr. Dietrich A. Ruess
Prof. Dr. Stefan Fichtner-Feigl
Guest Editors

Manuscript Submission Information

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Keywords

  • pancreatic ductal adenocarcinoma
  • actionable molecular mechanisms
  • translational
  • resection
  • radiation
  • chemotherapy
  • targeted therapy
  • immunotherapy
  • multimodal
  • personalized medicine

Published Papers (17 papers)

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Research

9 pages, 1017 KiB  
Article
Efficacy of Fully Covered Self-Expandable Metal Stents for Distal Biliary Obstruction Caused by Pancreatic Ductal Adenocarcinoma: Primary Metal Stent vs. Metal Stent following Plastic Stent
by Chi-Huan Wu, Sheng-Fu Wang, Mu-Hsien Lee, Yung-Kuan Tsou, Cheng-Hui Lin, Li-Ling Chang, Kai-Feng Sung and Nai-Jen Liu
Cancers 2023, 15(11), 3001; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15113001 - 31 May 2023
Viewed by 955
Abstract
Fully covered self-expandable metallic stents (FCSEMSs) are inserted in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) to resolve malignant distal bile duct obstructions. Some patients receive FCSEMSs during primary endoscopic retrograde cholangiopancreatography (ERCP), and others receive FCSEMSs during a later session, after the [...] Read more.
Fully covered self-expandable metallic stents (FCSEMSs) are inserted in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) to resolve malignant distal bile duct obstructions. Some patients receive FCSEMSs during primary endoscopic retrograde cholangiopancreatography (ERCP), and others receive FCSEMSs during a later session, after the placement of a plastic stent. We aimed to evaluate the efficacy of FCSEMSs for primary use or following plastic stent placement. A total of 159 patients with pancreatic adenocarcinoma (m:f, 102:57) who had achieved clinical success underwent ERCP with the placement of FCSEMSs for palliation of obstructive jaundice. One-hundred and three patients had received FCSEMSs in a first ERCP, and 56 had received FCSEMSs after prior plastic stenting. Twenty-two patients in the primary metal stent group and 18 in the prior plastic stent group had recurrent biliary obstruction (RBO). The RBO rates and self-expandable metal stent patency duration did not differ between the two groups. An FCSEMS longer than 6 cm was identified as a risk factor for RBO in patients with PDAC. Thus, choosing an appropriate FCSEMS length is an important factor in preventing FCSEMS dysfunction in patients with PDAC with malignant distal bile-duct obstruction. Full article
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15 pages, 3012 KiB  
Article
Targeting Interleukin-6/Glycoprotein-130 Signaling by Raloxifene or SC144 Enhances Paclitaxel Efficacy in Pancreatic Cancer
by Nina A. Hering, Emily Günzler, Marco Arndt, Miriam Zibell, Johannes C. Lauscher, Martin E. Kreis, Katharina Beyer, Hendrik Seeliger and Ioannis Pozios
Cancers 2023, 15(2), 456; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020456 - 11 Jan 2023
Cited by 4 | Viewed by 1728
Abstract
Interleukine-6 plays a key role in the progression and poor survival in pancreatic ductal adenocarcinoma (PDAC). The present study aimed to clarify if targeting the interleukin-6/glycoprotein-130 signaling cascade using the small-molecule gp130 inhibitor SC144 or raloxifene, a non-steroidal selective estrogen receptor modulator, enhances [...] Read more.
Interleukine-6 plays a key role in the progression and poor survival in pancreatic ductal adenocarcinoma (PDAC). The present study aimed to clarify if targeting the interleukin-6/glycoprotein-130 signaling cascade using the small-molecule gp130 inhibitor SC144 or raloxifene, a non-steroidal selective estrogen receptor modulator, enhances paclitaxel efficacy. MTT/BrdU assays or TUNEL staining were performed to investigate cell viability, proliferation and apoptosis induction in L3.6pl and AsPC-1 human pancreatic cell lines. In vivo, effects were studied in an orthotopic PDAC mouse model. Tumor specimens were analyzed by qPCR, immunohistochemistry and ELISA. Combination of paclitaxel/raloxifene, but not paclitaxel/SC144, enhanced proliferation and viability inhibition and increased apoptosis compared to single treatment in vitro. Synergy score calculations confirmed an additive influence of raloxifene on paclitaxel. In the PDAC mouse model, both combinations of raloxifene/paclitaxel and SC144/paclitaxel reduced tumor weight and volume compared to single-agent therapy or control. Raloxifene/paclitaxel treatment decreased survivin mRNA expression and showed tendencies of increased caspase-3 staining in primary tumors. SC144/paclitaxel reduced interleukin-6 levels in mice’s tumors and plasma. In conclusion, raloxifene or SC144 can enhance the anti-tumorigenic effects of paclitaxel, suggesting that paclitaxel doses might also be reduced in combined chemotherapy to lessen paclitaxel side effects. Full article
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14 pages, 644 KiB  
Article
Isotoxic High-Dose Stereotactic Body Radiotherapy (iHD-SBRT) Versus Conventional Chemoradiotherapy for Localized Pancreatic Cancer: A Single Cancer Center Evaluation
by Martin Manderlier, Julie Navez, Matthieu Hein, Jean-Luc Engelholm, Jean Closset, Maria Antonietta Bali, Dirk Van Gestel, Luigi Moretti, Jean-Luc Van Laethem and Christelle Bouchart
Cancers 2022, 14(23), 5730; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235730 - 22 Nov 2022
Cited by 6 | Viewed by 1274
Abstract
Given the lack of direct comparative evidence, we aimed to compare the oncological outcomes of localized pancreatic ductal adenocarcinoma (PDAC) treated in the same tertiary cancer center with isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) or conventional chemoradiotherapy (CRT). Biopsy-proven borderline/locally advanced patients treated [...] Read more.
Given the lack of direct comparative evidence, we aimed to compare the oncological outcomes of localized pancreatic ductal adenocarcinoma (PDAC) treated in the same tertiary cancer center with isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) or conventional chemoradiotherapy (CRT). Biopsy-proven borderline/locally advanced patients treated with iHD-SBRT (35 Gy in 5 fractions with a simultaneous integrated boost up to 53 Gy) or CRT (45–60 Gy in 25–30 fractions) were retrospectively included from January 2006 to January 2021. The median overall survival (mOS) was evaluated trough uni- and multivariate analyses. The progression free survival (PFS) and the 1-year local control (1-yLC) were also reported. Eighty-two patients were included. The median follow-up was 19.7 months. The mOS was in favour of the iHD-SBRT group (22.5 vs. 15.9 months, p < 0.001), including after multivariate analysis (HR 0.39 [CI95% 0.18–0.83], p = 0.014). The median PFS and the 1-yLC were also significantly better for iHD-SBRT (median PFS: 16.7 vs. 11.5 months, p = 0.011; 1-yLC: 75.8 vs. 39.3%, p = 0.004). In conclusion, iHD-SBRT is a promising RT option and may offer an improvement in OS in comparison to CRT for localized PDAC. Further validation is required to confirm the exact role of iHD-SBRT and the optimal therapeutic sequence for the treatment of localized PDAC. Full article
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10 pages, 1089 KiB  
Article
Levels of Evidence Supporting United States Guidelines in Pancreatic Adenocarcinoma Treatment
by Anna Pellat, Isabelle Boutron, Romain Coriat and Philippe Ravaud
Cancers 2022, 14(16), 4062; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14164062 - 22 Aug 2022
Cited by 1 | Viewed by 1489
Abstract
Cancer guidelines are ideally based on high levels of evidence (LOE). We aim to evaluate the LOE supporting recommendations in United States (US) guidelines on pancreatic adenocarcinoma (PDAC) treatment and its evolution over time. We searched for current guidelines from the American Society [...] Read more.
Cancer guidelines are ideally based on high levels of evidence (LOE). We aim to evaluate the LOE supporting recommendations in United States (US) guidelines on pancreatic adenocarcinoma (PDAC) treatment and its evolution over time. We searched for current guidelines from the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) and their prior publicly available versions on societies’ websites and/or MEDLINE. We recorded the LOE and class of recommendation (opinion of the writing panel) for each recommendation. We defined high LOE as: a “high” quality of evidence from the GRADE methodology (ASCO) and “Category 1” (NCCN). Our main outcome was the proportion of PDAC recommendations supported by high LOE. Proportions of high LOE recommendations were 5% (2/40) and 8% (12/153) in current ASCO and NCCN guidelines, respectively. Less than 10% of class I recommendations were based on high LOE. For NCCN guidelines, the proportion of high LOE recommendations did not improve over time and only three recommendations increased their LOE. We identified a small percentage of high LOE recommendations for PDAC treatment in US guidelines. However, guidelines authors can only deal with the available evidence. The current framework of evidence should be challenged with consideration of observational evidence. Full article
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11 pages, 421 KiB  
Article
Preneoplastic Lesions in Surgical Specimens Do Not Worsen the Prognosis of Patients Who Underwent Surgery for Pancreatic Adenocarcinoma: Post-Hoc Analysis of the PRODIGE 24-CCTG PA 6 Trial
by Théo Legrand, Julia Salleron, Thierry Conroy, Frédéric Marchal, Jacques Thomas, Laure Monard, James Jim Biagi and Aurélien Lambert
Cancers 2022, 14(16), 3945; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14163945 - 16 Aug 2022
Cited by 1 | Viewed by 1328
Abstract
Objective: The prognosis of pancreatic cancer after curative surgery is burdened by frequent recurrence. The aim of this study was to evaluate the impact of dysplasia in the surgical specimen on disease-free survival (DFS). Methods: A post-hoc analysis of the phase III PRODIGE [...] Read more.
Objective: The prognosis of pancreatic cancer after curative surgery is burdened by frequent recurrence. The aim of this study was to evaluate the impact of dysplasia in the surgical specimen on disease-free survival (DFS). Methods: A post-hoc analysis of the phase III PRODIGE 24-CCTG PA 6 trial was performed. From April 2012 to October 2016, 493 patients were included in the primary study. Assessment for dysplasia in the surgical specimens was secondarily performed. Dysplasia was defined based on presence and grade of three most common pre-malignant lesions (intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN) and pancreatic intraepithelial neoplasia (PanIN). The primary endpoint was DFS validated through multivariate analysis. Results: Two hundred twenty-six patients (45.9%) had a preneoplastic lesion. PanIN lesions were found in 193 patients (39.2%), including 100 high-grade lesions (20.6%); 43 patients had IPMN lesions (8.7%), including high-grade lesions in 32 (6.5%). Three MCN were described (0.6%). In bivariate analysis, the presence of dysplasia was not associated with poorer DFS (HR = 0.82, 95% CI [0.66; 1.03]). In multivariate analysis, risk factors for poorer DFS were poorly differentiated/undifferentiated tumor, N1 status, R1 surgical margins and perineural invasion. Conclusions: The presence of dysplasia in the surgical specimen after pancreatic cancer surgery does not worsen DFS. Full article
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18 pages, 2694 KiB  
Article
The Differential Clinical Impacts of Cachexia and Sarcopenia on the Prognosis of Advanced Pancreatic Cancer
by Ya-Chin Hou, Chien-Yu Chen, Chien-Jui Huang, Chih-Jung Wang, Ying-Jui Chao, Nai-Jung Chiang, Hao-Chen Wang, Hui-Ling Tung, Hsiao-Chun Liu and Yan-Shen Shan
Cancers 2022, 14(13), 3137; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133137 - 26 Jun 2022
Cited by 9 | Viewed by 2098
Abstract
Pancreatic cancer (PC) has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, which negatively influences patients’ outcome, quality of life, and tolerance/response to treatments. However, the clinical impacts of CC, SC, and their associated factors on outcomes for advanced PC has [...] Read more.
Pancreatic cancer (PC) has the highest frequency of developing cancer cachexia (CC)–sarcopenia (SC) syndrome, which negatively influences patients’ outcome, quality of life, and tolerance/response to treatments. However, the clinical impacts of CC, SC, and their associated factors on outcomes for advanced PC has yet to be fully investigated. A total of 232 patients were enrolled in this study for the retrospective review of their clinical information and the measurement of skeletal muscle areas at the third lumber vertebra by computed tomography scan to identify CC or SC. The association and concurrent occurrence of clinicopathological features in each patient, prevalence rates, and prognosis with the CC or SC were calculated. CC and SC were observed in 83.6% (n = 194) and 49.1% (n = 114) of PC patients, respectively. Low hemoglobin levels more often occurred in CC patients than in non-CC patients (p = 0.014). Older age (p = 0.000), female gender (p = 0.024), low body mass index (BMI) values (p = 0.004), low hemoglobin levels (p = 0.036), and low albumin levels (p = 0.001) were more often found in SC patients than in non-SC patients. Univariate and multivariate analyses showed that CC was an independent poor prognostic factor of overall survival (OS) and progression-free survival for all patients, the chemotherapy (C/T) subgroup, and the high BMI subgroup. Meanwhile, SC was an independent predictor of poor OS for the subgroups of C/T or high BMI but not for all patients. These findings reveal the clinical differences for CC and SC and provide useful information for predicting the prognosis of advanced PC patients and conducting personalized medicine. Full article
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21 pages, 3731 KiB  
Article
Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor
by Lara Diego-González, Andrea Fernández-Carrera, Ana Igea, Amparo Martínez-Pérez, M. Elisabete C. D. Real Oliveira, Andreia C. Gomes, Carmen Guerra, Mariano Barbacid, África González-Fernández and Rosana Simón-Vázquez
Cancers 2022, 14(13), 3102; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133102 - 24 Jun 2022
Cited by 3 | Viewed by 2626
Abstract
Pancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering [...] Read more.
Pancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering RNA (siRNA) to inhibit the combined expression of FOSL-1 and YAP, two signaling proteins related with tumor cell proliferation and survival. To improve the efficacy of cell transfection, DODAB:MO (1:2) liposomes were used as siRNA nanocarriers, forming a complex denominated siRNA-lipoplexes. Liposomes and lipoplexes (carrying two siRNA for each targeted protein, or the combination of four siRNAs) were physico-chemically and biologically characterized. They showed very good biocompatibility and stability. The efficient targeting of FOSL-1 and YAP expression at both mRNA and protein levels was first proved in vitro using mouse pancreatic tumoral cell lines (KRASG12V and p53 knockout), followed by in vivo studies using subcutaneous allografts on mice. The peri-tumoral injection of lipoplexes lead to a significant decrease in the tumor growth in both Athymic Nude-Foxn1nu and C57BL/6 mice, mainly in those receiving the combination of four siRNAs, targeting both YAP and FOSL-1. These results open a new perspective to overcome the fast tumor progression in pancreatic cancer. Full article
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12 pages, 991 KiB  
Article
ChemoSensitivity Assay Guided Metronomic Chemotherapy Is Safe and Effective for Treating Advanced Pancreatic Cancer
by William H. Isacoff, Brandon Cooper, Andrew Bartlett, Brian McCarthy and Kenneth H. Yu
Cancers 2022, 14(12), 2906; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122906 - 13 Jun 2022
Cited by 3 | Viewed by 2285
Abstract
Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients [...] Read more.
Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot (n = 50) and validation cohort (n = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician′s discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, p = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, p = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC. Full article
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16 pages, 1674 KiB  
Article
Can Surgical Resection of Metastatic Lesions Be Beneficial to Pancreatic Ductal Adenocarcinoma Patients with Isolated Lung Metastasis?
by Won-Gun Yun, Wooil Kwon, Youngmin Han, Hee Ju Sohn, Hyeong Seok Kim, Mirang Lee, Hongbeom Kim, Alexander S. Thomas, Michael D. Kluger and Jin-Young Jang
Cancers 2022, 14(9), 2067; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092067 - 20 Apr 2022
Cited by 7 | Viewed by 1807
Abstract
In the era of effective chemotherapy on pancreatic ductal adenocarcinoma (PDAC) with distant metastasis, data on the effects of metastatectomy are lacking. So, we investigated the effect of metastatectomy on survival after metastasis in PDAC patients with isolated lung metastasis. This retrospective study [...] Read more.
In the era of effective chemotherapy on pancreatic ductal adenocarcinoma (PDAC) with distant metastasis, data on the effects of metastatectomy are lacking. So, we investigated the effect of metastatectomy on survival after metastasis in PDAC patients with isolated lung metastasis. This retrospective study analyzed 1342 patients who were histologically diagnosed with PDAC with distant metastasis from January 2007 to December 2018, of which 83 patients had isolated pulmonary metastasis. Additionally, 4263 patients were extracted from the National Cancer Database (NCDB) and analyzed. Log-rank test and Kaplan−Meier survival analysis were used to analyze survival after metastasis. The five-year survival rate was significantly higher in patients who underwent pulmonary metastatectomy than in those who received only chemotherapy or supportive treatment (60.6% vs. 6.2% vs. 0.0%, p < 0.001). A similar trend was observed in the NCDB (two-year survival rate, 27.4% vs. 15.8% vs. 4.7%, p < 0.001). In the multivariate analysis, lung lesion multiplicity (hazard ratio (HR) = 2.004, p = 0.017), metastatectomy (HR = 0.278, p = 0.036), chemotherapy (HR = 0.434, p = 0.024), and chemotherapy cycles (HR = 0.300, p < 0.001) had significant effects on survival. Metastatectomy with primary pancreatic lesions is recommended with effective chemotherapy in PDAC patients with isolated lung metastasis. Full article
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16 pages, 4410 KiB  
Article
Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR)
by Raúl Muñoz Velasco, Paula Jiménez Sánchez, Ana García García, Raquel Blanco Martinez-Illescas, Ángela Pastor Senovilla, Marian Lozano Yagüe, Alfonsina Trento, Rosa María García-Martin, Diego Navarro, Bruno Sainz, Jr., José Luis Rodríguez Peralto and Víctor Javier Sánchez-Arévalo Lobo
Cancers 2022, 14(6), 1518; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061518 - 16 Mar 2022
Cited by 4 | Viewed by 2981
Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis due to its late diagnosis and strong chemoresistance to the current treatments. Therefore, finding new therapeutic targets is an urgent need nowadays. In this study, we report the role of the chromatin [...] Read more.
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis due to its late diagnosis and strong chemoresistance to the current treatments. Therefore, finding new therapeutic targets is an urgent need nowadays. In this study, we report the role of the chromatin remodeler BPTF (Bromodomain PHD Finger Transcription Factor) as a therapeutic target in PDA. BPTF-silencing dramatically reduced cell proliferation and migration in vitro and in vivo in human and mouse PDA cell lines. Moreover, BPTF-silencing reduces the IC50 of gemcitabine in vitro and enhanced its therapeutic effect in vivo. Mechanistically, BPTF is required for c-MYC recruitment to the promoter of ABC-transporters and its downregulation facilitates gemcitabine accumulation in tumour cells, increases DNA damage, and a generates a strong synergistic effect in vivo. We show that BPTF is a therapeutic target in pancreatic ductal adenocarcinoma due to its strong effect on proliferation and in response to gemcitabine. Full article
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24 pages, 4025 KiB  
Article
Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer Xenografts with FGFR and ALK Kinase Inhibitors
by Ivana Peran, Eveline E. Vietsch, Gai Yan, Anna T. Riegel and Anton Wellstein
Cancers 2022, 14(6), 1517; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061517 - 16 Mar 2022
Cited by 1 | Viewed by 2224
Abstract
Pancreatic adenocarcinoma is typically detected at a late stage and thus shows only limited sensitivity to treatment, making it one of the deadliest malignancies. In this study, we evaluate changes in microRNA (miR) patterns in peripheral blood as a potential readout of treatment [...] Read more.
Pancreatic adenocarcinoma is typically detected at a late stage and thus shows only limited sensitivity to treatment, making it one of the deadliest malignancies. In this study, we evaluate changes in microRNA (miR) patterns in peripheral blood as a potential readout of treatment responses of pancreatic cancer to inhibitors that target tumor–stroma interactions. Mice with pancreatic cancer cell (COLO357PL) xenografts were treated with inhibitors of either fibroblast growth factor receptor kinase (FGFR; PD173074) or anaplastic lymphoma kinase receptor (ALK; TAE684). While both treatments inhibited tumor angiogenesis, signal transduction, and mitogenesis to a similar extent, they resulted in distinct changes in circulating miR signatures. Comparison of the miR pattern in the tumor versus that in circulation showed that the inhibitors can be distinguished by their differential impact on tumor-derived miRs as well as host-derived circulating miRs. Distinct signatures that include circulating miR-1 and miR-22 are associated with the efficacy of ALK and FGFR inhibition, respectively. We propose that monitoring changes in circulating miR profiles can provide an early signature of treatment response or resistance to pathway-targeted drugs, and thus provide a non-invasive measurement to rapidly assess the efficacy of candidate therapies. Full article
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16 pages, 743 KiB  
Article
Impact of UGT1A1 Polymorphisms on Febrile Neutropenia in Pancreatic Cancer Patients Receiving FOLFIRINOX: A Single-Center Cohort Study
by Jiyoung Keum, Hee Seung Lee, Jung Hyun Jo, Moon Jae Chung, Jeong Youp Park, Seung Woo Park, Si Young Song and Seungmin Bang
Cancers 2022, 14(5), 1244; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051244 - 28 Feb 2022
Cited by 1 | Viewed by 1691
Abstract
FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil) is a first-line chemotherapy for metastatic pancreatic cancer (PC). Chemotherapy-induced neutropenia is one of the most serious adverse events associated with advanced PC. Although UGT1A1 polymorphisms are associated with the metabolism of irinotecan, their role as surrogate [...] Read more.
FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil) is a first-line chemotherapy for metastatic pancreatic cancer (PC). Chemotherapy-induced neutropenia is one of the most serious adverse events associated with advanced PC. Although UGT1A1 polymorphisms are associated with the metabolism of irinotecan, their role as surrogate markers for FOLFIRINOX-induced neutropenia has not been confirmed. We investigated risk factors for FN—in particular, UGT1A1 polymorphisms—in PC patients receiving FOLFIRINOX, using a single-center cohort registry. To investigate the association between UGT1A1 polymorphisms and FN, we divided patients into three groups based on the predicted UGT1A1 phenotype: extensive metabolizer (EM) vs. intermediate metabolizer (IM) vs. poor metabolizer (PM). A total of 154 patients (FN group (n = 31) vs. non-FN group (n = 123)) receiving first-line FOLFIRINOX were identified between December 2017 and July 2020. The Cox regression analysis showed that female sex (HR: 2.20; p = 0.031), Eastern Cooperative Oncology Group performance status = 1 (HR: 2.83; p = 0.008), UGT1A1 IM (HR: 4.30; p = 0.004), and UGT1A1 PM (HR: 4.03; p = 0.028) were statistically significant risk factors for FN. We propose that UGT1A1 is the strongest predictive factor for FN and that this gene should be screened prior to the administration of chemotherapy. Full article
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15 pages, 1459 KiB  
Article
Survival Benefit of Resection Surgery for Pancreatic Ductal Adenocarcinoma with Liver Metastases: A Propensity Score-Matched SEER Database Analysis
by Thomas M. Pausch, Xinchun Liu, Jiaqu Cui, Jishu Wei, Yi Miao, Ulrike Heger, Pascal Probst, Stephen Heap and Thilo Hackert
Cancers 2022, 14(1), 57; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010057 - 23 Dec 2021
Cited by 21 | Viewed by 3918
Abstract
Guidelines do not recommend resection surgery for oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, reports in small samples of selected patients suggest that surgery extends survival. Thus, this study aims to gather evidence for the benefits of cancer-directed surgery (CDS) by analyzing a national [...] Read more.
Guidelines do not recommend resection surgery for oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, reports in small samples of selected patients suggest that surgery extends survival. Thus, this study aims to gather evidence for the benefits of cancer-directed surgery (CDS) by analyzing a national cohort and identifying prognostic factors that aid the selection of candidates for CDS or recruitment into experimental trials. Data for patients with PDAC and hepatic metastasis were extracted from the population-based Surveillance, Epidemiology, and End Results database (SEER). The bias between CDS and non-CDS groups was minimized with Propensity Score Matching (PSM), and the prognostic role of CDS was investigated by comparing Kaplan-Meier estimators and Cox proportional hazard models. A total of 12,018 patients were extracted from the database, including 259 patients who underwent CDS that were 1:1 propensity score-matched with patients who did not receive CDS. CDS appeared to significantly prolong median overall survival from 5 to 10 months. Multivariate analysis revealed chemotherapy as a protective prognostic, whilst survival was impaired by old age and tumors that were poorly differentiated (Grades III–IV). These factors can be used to select patients likely to benefit from CDS treatment, which may facilitate recruitment into randomized controlled trials. Full article
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19 pages, 3680 KiB  
Article
Anticancer Effect of Heparin–Taurocholate Conjugate on Orthotopically Induced Exocrine and Endocrine Pancreatic Cancer
by Hae Hyun Hwang, Hee Jeong Jeong, Sangwu Yun, Youngro Byun, Teruo Okano, Sung Wan Kim and Dong Yun Lee
Cancers 2021, 13(22), 5775; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225775 - 18 Nov 2021
Cited by 3 | Viewed by 2347
Abstract
Pancreatic cancers are classified based on where they occur, and are grouped into those derived from exocrine and those derived from neuroendocrine tumors, thereby experiencing different anticancer effects under medication. Therefore, it is necessary to develop anticancer drugs that can inhibit both types. [...] Read more.
Pancreatic cancers are classified based on where they occur, and are grouped into those derived from exocrine and those derived from neuroendocrine tumors, thereby experiencing different anticancer effects under medication. Therefore, it is necessary to develop anticancer drugs that can inhibit both types. To this end, we developed a heparin–taurocholate conjugate, i.e., LHT, to suppress tumor growth via its antiangiogenic activity. Here, we conducted a study to determine the anticancer efficacy of LHT on pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET), in an orthotopic animal model. LHT reduced not only proliferation of cancer cells, but also attenuated the production of VEGF through ERK dephosphorylation. LHT effectively reduced the migration, invasion and tube formation of endothelial cells via dephosphorylation of VEGFR, ERK1/2, and FAK protein. Especially, these effects of LHT were much stronger on PNET (RINm cells) than PDAC (PANC1 and MIA PaCa-2 cells). Eventually, LHT reduced ~50% of the tumor weights and tumor volumes of all three cancer cells in the orthotopic model, via antiproliferation of cancer cells and antiangiogenesis of endothelial cells. Interestingly, LHT had a more dominant effect in the PNET-induced tumor model than in PDAC in vivo. Collectively, these findings demonstrated that LHT could be a potential antipancreatic cancer medication, regardless of pancreatic cancer types. Full article
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9 pages, 845 KiB  
Article
Clinical Characteristics of Resected Acinar Cell Carcinoma of the Pancreas: A Korean Multi-Institutional Study
by Sang Hyun Shin, Ho Kyoung Hwang, Jin-Young Jang, Hongbeom Kim, Sang Jae Park, Sung-Sik Han, In Woong Han, Dae Wook Hwang and Jin Seok Heo
Cancers 2021, 13(20), 5095; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205095 - 12 Oct 2021
Cited by 3 | Viewed by 1487
Abstract
Given the rare incidence of pancreatic acinar cell carcinoma (PACC), its post-resection clinical outcomes remain unclear. Treatment strategies for PACC have relied on those of pancreatic ductal adenocarcinoma (PDAC). The present study retrospectively investigated clinicopathologic characteristics of resected PACC registered in the Korea [...] Read more.
Given the rare incidence of pancreatic acinar cell carcinoma (PACC), its post-resection clinical outcomes remain unclear. Treatment strategies for PACC have relied on those of pancreatic ductal adenocarcinoma (PDAC). The present study retrospectively investigated clinicopathologic characteristics of resected PACC registered in the Korea Tumor Registry System Biliary Pancreas database. Among 59 patients with a mean age of 59.2 years and a male predominance (83.1%), 43, 5, 7, and 4 had pure PACC, ductal differentiations, mixed neuroendocrine carcinomas, and intraductal and papillary variants, respectively. The mean tumor size was 4.6 cm, consisting of eight at T1, 26 at T2, and 25 at T3 stages. Metastasis to regional lymph node was identified in 15 (25.4%) patients. Thirty-one (52.5%) patients received adjuvant therapy. Five-year survival rate was 57.4%. The median survival was 78.8 months. In survival comparison according to the stage with AJCC system, N stage (lymph node metastasis), but not T stage, showed significant differences (p = 0.027). Resected PACC appeared to have clinical outcomes distinct from those of PDAC in this nationwide study. Therefore, large-scale multinational studies are needed to overcome the rarity of PACC and to establish an appropriate treatment strategies and staging system. Full article
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11 pages, 1253 KiB  
Article
The Survival Benefit of Chemoradiotherapy following Induction Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Unresectable Locally Advanced Pancreatic Cancer
by Ryoji Takada, Kenji Ikezawa, Kazuma Daiku, Shingo Maeda, Yutaro Abe, Makiko Urabe, Yugo Kai, Takuo Yamai, Nobuyasu Fukutake, Tasuku Nakabori, Hiroyuki Uehara, Reiko Ashida, Hirofumi Akita, Hidenori Takahashi, Teruki Teshima and Kazuyoshi Ohkawa
Cancers 2021, 13(18), 4733; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184733 - 21 Sep 2021
Cited by 13 | Viewed by 2583
Abstract
An optimal therapeutic strategy for unresectable locally advanced pancreatic cancer (UR-LAPC) has not been established. This study investigated the therapeutic efficacy of chemoradiotherapy (CRT) following induction chemotherapy with gemcitabine plus nab-paclitaxel (GnP) (CRT group) compared with systemic chemotherapy alone (CTx group) in patients [...] Read more.
An optimal therapeutic strategy for unresectable locally advanced pancreatic cancer (UR-LAPC) has not been established. This study investigated the therapeutic efficacy of chemoradiotherapy (CRT) following induction chemotherapy with gemcitabine plus nab-paclitaxel (GnP) (CRT group) compared with systemic chemotherapy alone (CTx group) in patients with UR-LAPC. This was a retrospective study of 63 consecutive patients with UR-LAPC treated at our department in a Japanese cancer referral center between February 2015 and July 2018. We excluded patients who underwent other regimens and those enrolled in another prospective study. The CRT group (n = 25) exhibited significantly better progression-free survival (PFS) and overall survival (OS) than the CTx group (n = 20, PFS 17.9 vs. 7.6 months, p = 0.044; OS 29.2 vs. 17.4 months, p < 0.001). In the multivariate analyses, CRT following induction chemotherapy was identified as an independent prognostic factor for OS. Seven (15.6%) patients underwent conversion surgery, all of whom were in the CRT group. The R0 resection rate was 85.7% (6/7). In summary, patients with UR-LAPC experienced favorable treatment outcomes after receiving GnP as the first-line chemotherapy, especially when receiving additional CRT. Thus, this treatment strategy represents a promising treatment option for selected patients with UR-LAPC. Full article
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25 pages, 7780 KiB  
Article
Heme Oxygenase-1 Inhibition Potentiates the Effects of Nab-Paclitaxel-Gemcitabine and Modulates the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma
by Iman M. Ahmad, Alicia J. Dafferner, Kelly A. O’Connell, Kamiya Mehla, Bradley E. Britigan, Michael A. Hollingsworth and Maher Y. Abdalla
Cancers 2021, 13(9), 2264; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092264 - 08 May 2021
Cited by 14 | Viewed by 2787
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Tumor hypoxia plays an active role in promoting tumor progression, malignancy, and resistance to therapy in PDAC. We present evidence that nab-paclitaxel–gemcitabine (NPG) and/or a hypoxic tumor microenvironment (TME) up-regulate heme [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Tumor hypoxia plays an active role in promoting tumor progression, malignancy, and resistance to therapy in PDAC. We present evidence that nab-paclitaxel–gemcitabine (NPG) and/or a hypoxic tumor microenvironment (TME) up-regulate heme oxygenase-1 (HO-1), providing a survival advantage for tumors. Using PDAC cells in vitro and a PDAC mouse model, we found that NPG chemotherapy up-regulated expression of HO-1 in PDAC cells and increased its nuclear translocation. Inhibition of HO-1 with ZnPP and SnPP sensitized PDAC cells to NPG-induced cytotoxicity (p < 0.05) and increased apoptosis (p < 0.05). Additionally, HO-1 expression was increased in gemcitabine-resistant PDAC cells (p < 0.05), and HO-1 inhibition increased GEM-resistant PDAC sensitivity to NPG (p < 0.05). NPG combined with HO-1 inhibitor inhibited tumor size in an orthotopic model. In parallel, HO-1 inhibition abrogated the influx of macrophages and FoxP3+ cells, while increasing the proportion of CD8+ infiltration in the pancreatic tumors. These effects were mediated primarily by reducing expression of the immunosuppressive cytokine IL-10. Full article
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