Special Issue "Advances in Pancreatic Cancer Research"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 May 2019

Special Issue Editors

Guest Editor
Dr. Nicola Silvestris

Cancer Institute "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy
Website | E-Mail
Interests: gastrointestinal tumors, translational research, clinical trials
Guest Editor
Dr. Oronzo Brunetti

Medical Oncology Unit, Hospital of Barletta, Barletta, Italy
Website | E-Mail
Interests: gastrointestinal tumors, translational research, clinical trials

Special Issue Information

Dear Colleagues,

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most challenging human cancers to be treated, with projections foreseeing it becoming the second leading cause of cancer death by 2030 in both Europe and the United States. Furthermore, neuroendocrine pancreatic tumors (pNETs) are heterogeneous malignancies, and their incidence has steadily increased in the last three decades. Although many studies have been carried out on these malignancies, the currently available treatments do not obtain suitable results. Hence, novel research strategies are needed to better define diagnostic and therapeutic algorithms for the next decade.

The focus of this Special Issue is to consider the following research aspects of both PDAC and pNET: a) primary and secondary prevention; b) biology and genomic characterization; c) innovations in multidisciplinary management including diagnosis, surgery, radiotherapy, and chemotherapy in the adjuvant, neoadjuvant and metastatic settings; d) molecularly-targeted drugs and immunotherapy.

Dr. Nicola Silvestris
Dr. Oronzo Brunetti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pancreatic ductal adenocarcinoma
  • pancreatic neuroendocrine tumor
  • prevention
  • biology and genomic characterization
  • diagnosis
  • surgery
  • radiotherapy
  • chemotherapy
  • targeted drugs
  • immunotherapy
  • translational research

Published Papers (10 papers)

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Research

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Open AccessArticle CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer
Cancers 2019, 11(3), 330; https://doi.org/10.3390/cancers11030330
Received: 23 January 2019 / Revised: 1 March 2019 / Accepted: 1 March 2019 / Published: 7 March 2019
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Abstract
Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the [...] Read more.
Tumor–stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the effect on tumor invasion and angiogenesis were evaluated with or without a conditioned medium from the mast cell line HMC-1 (human mast cell line-1 cells) and CAFs. Beside the clinical outcome of a homogenous population of PDAC patients, receiving GEM/NAB, was correlated to the circulating levels of mast cell tryptase and to a panel of inflammatory and immunosuppressive cytokines. CAFs neither affected drugs’ cytotoxicity nor the inhibition of angiogenesis, but promoted tumor cell invasion. The MC instead, caused resistance to drugs by reducing apoptosis, by activating the TGF-β signalling and by promoting tumor invasion. Indeed, the inhibition of TβRI serine/threonine kinase activity by galunisertib restored drugs cytotoxicity. Moreover, MC induced the release of TGF-β1, and increased expression of PAR-2, ERK1/2 and Akt activation. Accordingly, TGF-β1, tryptase and other pro-inflammatory and immunosuppressive cytokines increased in the unresponsive patients. In conclusion, MC play a pivotal role in the resistance to GEM/NAB. A correlation between high level of circulating pro-inflammatory/ immunosuppressive cytokines and unresponsiveness was found in PDAC patients. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Open AccessArticle Clinical Outcomes of Conversion Surgery after Neoadjuvant Chemotherapy in Patients with Borderline Resectable and Locally Advanced Unresectable Pancreatic Cancer: A Single-Center, Retrospective Analysis
Cancers 2019, 11(3), 278; https://doi.org/10.3390/cancers11030278
Received: 24 December 2018 / Revised: 12 February 2019 / Accepted: 24 February 2019 / Published: 26 February 2019
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Abstract
The clinical benefit and potential risks of conversion surgery after neoadjuvant chemotherapy (NACT) have not been fully investigated in patients with borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). Therefore, this has been evaluated in a retrospective, prospective cohort-based [...] Read more.
The clinical benefit and potential risks of conversion surgery after neoadjuvant chemotherapy (NACT) have not been fully investigated in patients with borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). Therefore, this has been evaluated in a retrospective, prospective cohort-based analysis. Between October 2005 and April 2017, 135 patients (65 with BRPC and 70 with LAPC) received conversion surgery after NACT. Exploratory analysis to assess clinical outcomes in comparison with patients who underwent upfront surgery in the same time period (n = 359) was also conducted. NACT with gemcitabine-based regimens (including gemcitabine monotherapy, gemcitabine-capecitabine combination, and gemcitabine-erlotinib combination) was used in 69 patients (51%) and FOLFIRINOX in 66 patients (49%). The median overall survival (OS) and disease-free survival (DFS) from the time of surgery was 25.4 months (95% CI, 18.6–32.2 months) and 9.0 months (95% CI, 6.8–11.2 months), respectively. The median OS and progression-free survival from the initiation of NACT was 29.7 months (95% CI, 22.5–36.8 months) and 13.4 months (95% CI, 12.5–14.4 months), respectively. In the exploratory analysis, conversion surgery after NACT was associated with a better median OS and DFS than upfront surgery (vs. 17.1 months; 95% CI, 15.5–18.7 months; p = 0.001 and vs. 7.1 months; 95% CI, 6.4–7.8 months; p = 0.005, respectively). There was no difference in length of hospital stay between the two groups, and conversion surgery after NACT showed a significantly lower incidence of postoperative complications than upfront surgery (38% vs. 27%, p = 0.03). Conversion surgery after NACT is a feasible and effective therapeutic strategy for the treatment of patients with BRPC and LAPC. Further clinical trials investigating optimal therapeutic strategies for BRPC and LAPC are warranted. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Open AccessArticle Preoperative Imaging Evaluation after Downstaging of Pancreatic Ductal Adenocarcinoma: A Multi-Center Study
Cancers 2019, 11(2), 267; https://doi.org/10.3390/cancers11020267
Received: 20 January 2019 / Revised: 12 February 2019 / Accepted: 19 February 2019 / Published: 25 February 2019
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Abstract
Introduction: Evaluation of pancreatic ductal adenocarcinoma (PDAC) after chemoradiotherapy downstaging is challenging due to computed tomography (CT) overestimation of tumor extension and residual vascular involvement, limiting access to surgery to some patients with potentially resectable tumors. With this study, we wanted to assess [...] Read more.
Introduction: Evaluation of pancreatic ductal adenocarcinoma (PDAC) after chemoradiotherapy downstaging is challenging due to computed tomography (CT) overestimation of tumor extension and residual vascular involvement, limiting access to surgery to some patients with potentially resectable tumors. With this study, we wanted to assess which radiological findings are most reliable at pre-operative imaging in the evaluation of PDAC after chemoradiotherapy in order to achieve complete resection. Methods: We retrospectively enrolled 71 patients with locally advanced and borderline resectable PDAC who underwent neoadjuvant chemoradiotherapy. Pre-operative CT or magnetic resonance (MR) have been evaluated by three radiologists to assess major qualitative and quantitative parameters of lesions. Accuracy, sensitivity, and specificity compared to anatomopathological results were evaluated for each parameter. Cohen’s K-coefficient has been calculated to evaluate the inter-observer agreement (IOA). Both single and consensus lecture have been tested. Different dimensional cut-offs were tested to categorize tumors according to their major axis and to compare with anatomopathological diameter, tumor persistence, and margin infiltration. Results: A 25 mm cut-off was 67% sensitive, 90% specific, and 77% accurate in assessing real tumor dimension. 25 mm cut-off reported a 64% sensitivity, 78% specificity, and 69% accuracy in assessing R0 resection. Each 5 mm increment of major axis dimension there is an odds ratio (OR) 1.79 (95% CI 1.13–2.80, p = 0.012) for R+ resection. Imaging presence of the perivascular cuff is not associated with tumor persistence and resection margin infiltration (p = 0.362). Lesion enhancement and pattern homogeneity were not accurate in determining tumor persistence. IOA was generally poor to fair, except for >25 mm cut-off classification where IOA was moderate. Diagnostic accuracy is superior in consensus lecture rather than single lecture. Conclusion: Imaging methods tend to underestimate PDAC resectability after neoadjuvant-CRT. IOA is poor to fair in evaluating most of the qualitative parameters of downstaged pancreatic adenocarcinoma. Surgery should be considered for downstaged borderline resectable PDACs, independently from perivascular cuff presence, especially for tumors smaller than 25 mm. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Open AccessArticle An Integrative Data Mining and Omics-Based Translational Model for the Identification and Validation of Oncogenic Biomarkers of Pancreatic Cancer
Cancers 2019, 11(2), 155; https://doi.org/10.3390/cancers11020155
Received: 14 December 2018 / Revised: 18 January 2019 / Accepted: 21 January 2019 / Published: 29 January 2019
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Abstract
Substantial alterations at the multi-omics level of pancreatic cancer (PC) impede the possibility to diagnose and treat patients in early stages. Herein, we conducted an integrative omics-based translational analysis, utilizing next-generation sequencing, transcriptome meta-analysis, and immunohistochemistry, combined with statistical learning, to validate multiplex [...] Read more.
Substantial alterations at the multi-omics level of pancreatic cancer (PC) impede the possibility to diagnose and treat patients in early stages. Herein, we conducted an integrative omics-based translational analysis, utilizing next-generation sequencing, transcriptome meta-analysis, and immunohistochemistry, combined with statistical learning, to validate multiplex biomarker candidates for the diagnosis, prognosis, and management of PC. Experiment-based validation was conducted and supportive evidence for the essentiality of the candidates in PC were found at gene expression or protein level by practical biochemical methods. Remarkably, the random forests (RF) model exhibited an excellent diagnostic performance and LAMC2, ANXA2, ADAM9, and APLP2 greatly influenced its decisions. An explanation approach for the RF model was successfully constructed. Moreover, protein expression of LAMC2, ANXA2, ADAM9, and APLP2 was found correlated and significantly higher in PC patients in independent cohorts. Survival analysis revealed that patients with high expression of ADAM9 (Hazard ratio (HR)OS = 2.2, p-value < 0.001), ANXA2 (HROS = 2.1, p-value < 0.001), and LAMC2 (HRDFS = 1.8, p-value = 0.012) exhibited poorer survival rates. In conclusion, we successfully explore hidden biological insights from large-scale omics data and suggest that LAMC2, ANXA2, ADAM9, and APLP2 are robust biomarkers for early diagnosis, prognosis, and management for PC. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Open AccessArticle Prognostic Factors for Advanced Pancreatic Cancer Treated with Gemcitabine Plus S-1: Retrospective Analysis and Development of a Prognostic Model
Received: 30 November 2018 / Revised: 4 January 2019 / Accepted: 7 January 2019 / Published: 9 January 2019
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Abstract
Gemcitabine plus S-1 (GS) is commonly used to treat advanced pancreatic cancer (APC) in Asia. Few clinical experiments have demonstrated the clinical efficacy of GS in routine clinical practice. We aimed to identify the prognostic factors and develop a prognostic model for survival [...] Read more.
Gemcitabine plus S-1 (GS) is commonly used to treat advanced pancreatic cancer (APC) in Asia. Few clinical experiments have demonstrated the clinical efficacy of GS in routine clinical practice. We aimed to identify the prognostic factors and develop a prognostic model for survival prediction in patients with APC, treated with GS. Records of 111 patients with newly diagnosed APC who received first-line palliative GS chemotherapy during 2010–2016 in Taiwan were analyzed retrospectively. Univariate and multivariate analyses were performed for the identification of prognostic factors. A prognostic model using prognosticators from the multivariate analysis was developed for survival prediction. The median overall survival (OS) for the cohort was 9.3 months (95% confidence interval [CI], 8.0–10.6). The prognostic model was constructed based on four independent prognosticators: performance status, tumor stage, pre-treatment albumin level, and neutrophil-to-lymphocyte ratio. Patients were categorized by tertiles into good, intermediate, and poor prognostic groups. The median OS values for each of these groups were 21.1 (95% CI, 8.2–33.9), 9.2 (95% CI, 8.3–10.1), and 5.8 months (95% CI, 4.4–7.1; log-rank p < 0.001), respectively. The bootstrapped corrected C-index of this model was 0.80 (95% CI, 0.71–0.89). The developed model was robust and could accurately predict survival in this population, and can assist clinicians and patients in survival discrimination and the determination of appropriate medical care goals. Additional research is needed to externally validate the model’s performance. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Open AccessArticle Venous Thromboembolism in Asian Patients with Pancreatic Cancer Following Palliative Chemotherapy: Low Incidence but a Negative Prognosticator for Those with Early Onset
Cancers 2018, 10(12), 501; https://doi.org/10.3390/cancers10120501
Received: 30 October 2018 / Revised: 30 November 2018 / Accepted: 9 December 2018 / Published: 10 December 2018
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Abstract
Background: Few studies have reported the epidemiology and clinical outcome of venous thromboembolism (VTE) in Asian patients with pancreatic cancer. This study investigated the incidence, risk factors, and clinical outcome of VTE in patients with pancreatic cancer following palliative chemotherapy. Methods: The medical [...] Read more.
Background: Few studies have reported the epidemiology and clinical outcome of venous thromboembolism (VTE) in Asian patients with pancreatic cancer. This study investigated the incidence, risk factors, and clinical outcome of VTE in patients with pancreatic cancer following palliative chemotherapy. Methods: The medical records of 838 patients with newly diagnosed locally advanced or metastatic pancreatic cancer who underwent palliative chemotherapy between 2010 and 2016 at four institutes in Taiwan were retrospectively reviewed. The clinical characteristics of all patients were analyzed to identify independent predictors of VTE and their effects on survival outcome. Results: During the median follow-up period of 7.7 months (range, 0.6–55.6), VTE occurred in 67 (8.0%) of the 838 patients. Leukocyte count > 11,000/μL and presence of liver metastases were the independent predictors of VTE. Patients with VTE did not show significantly poorer survival outcomes than those without VTE. However, early-onset VTE that occurred within 1.5 months after chemotherapy initiation was an independent negative prognosticator for overall survival. Conclusion: VTE incidence was found to be lower in Asian patients with pancreatic cancer than in their Western counterparts. Early-onset VTE, but not late-onset VTE, is a negative prognosticator for survival outcomes. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Review

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Open AccessReview Angiogenesis in Pancreatic Cancer: Pre-Clinical and Clinical Studies
Cancers 2019, 11(3), 381; https://doi.org/10.3390/cancers11030381
Received: 11 February 2019 / Revised: 11 March 2019 / Accepted: 14 March 2019 / Published: 18 March 2019
PDF Full-text (421 KB)
Abstract
Angiogenesis is a crucial event in tumor development and progression, occurring by different mechanisms and it is driven by pro- and anti-angiogenic molecules. Pancreatic cancer vascularization is characterized by a high microvascular density, impaired microvessel integrity and poor perfused vessels with heterogeneous distribution. [...] Read more.
Angiogenesis is a crucial event in tumor development and progression, occurring by different mechanisms and it is driven by pro- and anti-angiogenic molecules. Pancreatic cancer vascularization is characterized by a high microvascular density, impaired microvessel integrity and poor perfused vessels with heterogeneous distribution. In this review article, after a brief introduction on pancreatic cancer classification and on angiogenesis mechanisms involved in its progression, the pre-clinical and clinical trials conducted in pancreatic cancer treatment using anti-angiogenic inhibitors will be described. Finally, we will discuss the anti-angiogenic therapy paradox between the advantage to abolish vessel supply to block tumor growth and the disadvantage due to reduction of drug delivery at the same time. The purpose is to identify new anti-angiogenic molecules that may enhance treatment regimen. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
Open AccessReview Cancer-Associated Fibroblasts’ Functional Heterogeneity in Pancreatic Ductal Adenocarcinoma
Cancers 2019, 11(3), 290; https://doi.org/10.3390/cancers11030290
Received: 11 February 2019 / Revised: 22 February 2019 / Accepted: 26 February 2019 / Published: 1 March 2019
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths in the USA. Desmoplasia and inflammation are two major hallmarks of PDAC. Desmoplasia, composed of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), and infiltrating immune and endothelial cells, acts as a biophysical barrier to hinder chemotherapy and actively contributes to tumor progression and metastasis. CAFs represent a multifunctional subset of PDAC microenvironment and contribute to tumor initiation and progression through ECM deposition and remodeling, as well as the secretion of paracrine factors. Attempts to resolve desmoplasia by targeting CAFs can render an adverse outcome, which is likely due to CAFs heterogeneity. Recent reports describe subsets of CAFs that assume more secretory functions, in addition to the typical myofibroblast phenotype. Here, we review the literature and describe the relationship between CAFs and inflammation and the role of the secretory-CAFs in PDAC. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Open AccessReview Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition
Cancers 2019, 11(1), 113; https://doi.org/10.3390/cancers11010113
Received: 11 December 2018 / Revised: 15 January 2019 / Accepted: 17 January 2019 / Published: 19 January 2019
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Abstract
This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested [...] Read more.
This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13–1.88, p = 0.004; HR, 2.65; 95% CI, 1.79–3.91; p < 0.0001) and of recurrence (RR, 1.61; 95% CI, 1.05–2.47, p = 0.03) for PDAC patients with high-grade TB. Moreover, we found that EMT is a central process in determining the presence of TB in PDAC. Thanks to this meta-analysis, we demonstrate the potential clinical significance of high-grade TB for prognostic stratification of PDAC. TB also shows a clear association with the process of EMT. Based on the results of the present study, TB should be conveyed in pathology reports and taken into account by future oncologic staging systems. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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Open AccessReview Circulating Biomarkers for Prediction of Objective Response to Chemotherapy in Pancreatic Cancer Patients
Received: 4 December 2018 / Revised: 3 January 2019 / Accepted: 11 January 2019 / Published: 15 January 2019
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Abstract
Pancreatic cancer is a lethal disease with increasing incidence. Most patients present with advanced disease, for which palliative systemic chemotherapy is the only therapeutic option. Despite improved median survival rates with FOLFIRINOX or gemcitabine chemotherapy compared to the best supportive care, many individual [...] Read more.
Pancreatic cancer is a lethal disease with increasing incidence. Most patients present with advanced disease, for which palliative systemic chemotherapy is the only therapeutic option. Despite improved median survival rates with FOLFIRINOX or gemcitabine chemotherapy compared to the best supportive care, many individual patients may not benefit from chemotherapy. Biomarkers are needed to predict who will benefit from chemotherapy and to monitor a patient’s response to chemotherapy. This review summarizes current research and future perspectives on circulating biomarkers for systemic chemotherapy response. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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