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Advances in Diagnosis and Treatment of Pancreatic Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 31587

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Prof. Dr. Matthias Gaida

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Guest Editor

Institute for Pathology, University Medical Center Mainz, 55131 Mainz, Germany
Interests: pancreatic cancer; tumor microenvironment; tumor immunology; pathology
Special Issues, Collections and Topics in MDPI journals

Dr. Philipp Mayer

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Guest Editor

Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
Interests: CT and MR imaging; pancreatic cancer; hepatic cancers

Special Issue Information

Dear Colleagues,

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with progressively increasing incidence. Due to unspecific symptoms in its early stages and the absence of reliable diagnostic markers for early detection, PDAC often remains undiagnosed until late in the disease when the tumor has already progressed beyond the pancreas. In cases of invasion of the surrounding major visceral blood vessels or systemic spread, upfront surgery is often not possible or indicated. In some patients, modern (radio-) chemotherapy regimens may downstage the disease and facilitate the resectability of initially unresectable tumors (conversion surgery). For a large percentage of patients with progressed and/or metastatic disease, several novel (personalized) treatment strategies are currently being investigated, including therapies targeting the cancer cell metabolism or components of the tumor micromilieu and stroma. Improvements in histopathological and molecular tissue analysis, radiological imaging and image analysis as well as improved knowledge of radio-pathological correlation help to tailor these novel therapies to the individual patient, thus enhancing patient prognosis.

In this Special Issue of Cancers, we invite authors to contribute original research and review articles focusing on advances in radiological, histopathological, molecular, and genomic diagnostics as well as medical and surgical therapy of pancreatic cancer.

We look forward receiving your contributions.

Prof. Dr. Matthias Gaida
Dr. Philipp Mayer
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 submissions that pass pre-check are 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 semimonthly 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 2900 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 cancer
imaging
molecular diagnostics
histology
tumor heterogeneity
novel therapies
surgery

Published Papers (11 papers)

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Research

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14 pages, 1325 KiB

Open AccessArticle

Annotation-Efficient Deep Learning Model for Pancreatic Cancer Diagnosis and Classification Using CT Images: A Retrospective Diagnostic Study

by Thanaporn Viriyasaranon, Jung Won Chun, Young Hwan Koh, Jae Hee Cho, Min Kyu Jung, Seong-Hun Kim, Hyo Jung Kim, Woo Jin Lee, Jang-Hwan Choi and Sang Myung Woo

Cancers 2023, 15(13), 3392; https://doi.org/10.3390/cancers15133392 - 28 Jun 2023

Cited by 2 | Viewed by 1607

Abstract

The aim of this study was to develop a novel deep learning (DL) model without requiring large-annotated training datasets for detecting pancreatic cancer (PC) using computed tomography (CT) images. This retrospective diagnostic study was conducted using CT images collected from 2004 and 2019 from 4287 patients diagnosed with PC. We proposed a self-supervised learning algorithm (pseudo-lesion segmentation (PS)) for PC classification, which was trained with and without PS and validated on randomly divided training and validation sets. We further performed cross-racial external validation using open-access CT images from 361 patients. For internal validation, the accuracy and sensitivity for PC classification were 94.3% (92.8–95.4%) and 92.5% (90.0–94.4%), and 95.7% (94.5–96.7%) and 99.3 (98.4–99.7%) for the convolutional neural network (CNN) and transformer-based DL models (both with PS), respectively. Implementing PS on a small-sized training dataset (randomly sampled 10%) increased accuracy by 20.5% and sensitivity by 37.0%. For external validation, the accuracy and sensitivity were 82.5% (78.3–86.1%) and 81.7% (77.3–85.4%) and 87.8% (84.0–90.8%) and 86.5% (82.3–89.8%) for the CNN and transformer-based DL models (both with PS), respectively. PS self-supervised learning can increase DL-based PC classification performance, reliability, and robustness of the model for unseen, and even small, datasets. The proposed DL model is potentially useful for PC diagnosis. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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14 pages, 1776 KiB

Open AccessArticle

Identification and Validation of Potentially Clinically Relevant CpG Regions within the Class 2 Tumor Suppressor Gene SFRP1 in Pancreatic Cancer

by Maximilian Hauschulz, Sophia Villwock, Jennifer Kosinski, Florian Steib, Lara Rosaline Heij, Jan Bednarsch, Ruth Knüchel-Clarke and Edgar Dahl

Cancers 2023, 15(3), 683; https://doi.org/10.3390/cancers15030683 - 22 Jan 2023

Cited by 4 | Viewed by 1903

Abstract

In pancreatic cancer treatment, tumor stage-dependent chemotherapies are used to prolong overall survival. By measuring DNA promoter hypermethylation in the plasma of patients with stage IV pancreatic cancer, it was recently shown that promoter DNA methylation of the tumor suppressor gene SFRP1 has a high value for predicting failure of drug treatment with gemcitabine. In this study, we therefore aimed to identify as precisely as possible the region in the SFRP1 promoter that is frequently hypermethylated in pancreatic cancer tissue. First, we used the TCGA data set to define CpG-rich regions flanking the SFRP1 transcription start site that were significantly more methylated in pancreatic cancer compared to normal pancreatic acinar tissue. A core CpG island was identified that exhibited abundant tumor DNA methylation and anti-correlation of SFRP1 mRNA expression. To validate our in silico results, we performed bisulfide conversion followed by DNA pyrosequencing of 28 matched formalin-fixed, paraffin-embedded (FFPE) pancreatic cancer cases and six pancreatic cancer cell lines. A defined block of seven CpG sites within the core CpG island was identified, which confirmed our in silico results by showing significantly higher SFRP1 methylation in pancreatic cancer specimens than in normal pancreatic tissue. By selecting this core CpG island, we were able to determine a median overall survival benefit for the low SFRP1 methylation group compared to the high SFRP1 methylation group (702 versus 517 days, p = 0.01) in the TCGA pancreatic cancer cohort. We propose a compact pyrosequencing assay that can be used in the future to further investigate the prognostic value of SFRP1 promoter hypermethylation in predicting pancreatic cancer chemoresistance. Therefore, instead of DNA analysis from blood (liquid biopsy), DNA easily extractable from cancer tissue blocks (FFPE material) could be used. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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12 pages, 828 KiB

Open AccessArticle

CT Radiomics and Whole Genome Sequencing in Patients with Pancreatic Ductal Adenocarcinoma: Predictive Radiogenomics Modeling

by Ricarda Hinzpeter, Roshini Kulanthaivelu, Andres Kohan, Lisa Avery, Nhu-An Pham, Claudia Ortega, Ur Metser, Masoom Haider and Patrick Veit-Haibach

Cancers 2022, 14(24), 6224; https://doi.org/10.3390/cancers14246224 - 16 Dec 2022

Cited by 2 | Viewed by 1369

Abstract

We investigate whether computed tomography (CT) derived radiomics may correlate with driver gene mutations in patients with pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, 47 patients (mean age 64 ± 11 years; range: 42–86 years) with PDAC, who were treated surgically and who underwent preoperative CT imaging at our institution were included in the study. Image segmentation and feature extraction was performed semi-automatically with a commonly used open-source software platform. Genomic data from whole genome sequencing (WGS) were collected from our institution’s web-based resource. Two statistical models were then built, in order to evaluate the predictive ability of CT-derived radiomics feature for driver gene mutations in PDAC. 30/47 of all tumor samples harbored 2 or more gene mutations. Overall, 81% of tumor samples demonstrated mutations in KRAS, 68% of samples had alterations in TP53, 26% in SMAD4 and 19% in CDKN2A. Extended statistical analysis revealed acceptable predictive ability for KRAS and TP53 (Youden Index 0.56 and 0.67, respectively) and mild to acceptable predictive signal for SMAD4 and CDKN2A (Youden Index 0.5, respectively). Our study establishes acceptable correlation of radiomics features and driver gene mutations in PDAC, indicating an acceptable prognostication of genomic profiles using CT-derived radiomics. A larger and more homogenous cohort may further enhance the predictive ability. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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13 pages, 964 KiB

Open AccessFeature PaperArticle

Use of Autoreactive Antibodies in Blood of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) for Grade Distinction and Detection of Malignancy

by Niall Brindl, Henning Boekhoff, Andrea S. Bauer, Matthias M. Gaida, Hien T. Dang, Jörg Kaiser, Jörg D. Hoheisel and Klaus Felix

Cancers 2022, 14(15), 3562; https://doi.org/10.3390/cancers14153562 - 22 Jul 2022

Cited by 1 | Viewed by 1668

Abstract

(1) Background: A reliable non-invasive distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMN) is needed to effectively detect IPMN with malignant potential. This would improve preventative care and reduce the risk of developing pancreatic cancer and overtreatment. The present study aimed at exploring the presence of autoreactive antibodies in the blood of patients with IPMN of various grades of dysplasia. (2) Methods: A single-center cohort was studied composed of 378 serum samples from patients with low-grade IPMN (n = 91), high-grade IPMN (n = 66), IPMN with associated invasive cancer (n = 30), pancreatic ductal adenocarcinoma (PDAC) stages T1 (n = 24) and T2 (n = 113), and healthy controls (n = 54). A 249 full-length recombinant human protein microarray was used for profiling the serum samples. (3) Results: 14 proteins were identified as potential biomarkers for grade distinction in IPMN, yielding high specificity but mediocre sensitivity. (4) Conclusions: The identified autoantibodies are potential biomarkers that may assist in the detection of malignancy in IPMN patients. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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15 pages, 3114 KiB

Open AccessArticle

Liquid Biopsy for Pancreatic Cancer Detection Using Infrared Spectroscopy

by Alexandra Sala, James M. Cameron, Cerys A. Jenkins, Hugh Barr, Loren Christie, Justin J. A. Conn, Thomas R. Jeffry Evans, Dean A. Harris, David S. Palmer, Christopher Rinaldi, Ashton G. Theakstone and Matthew J. Baker

Cancers 2022, 14(13), 3048; https://doi.org/10.3390/cancers14133048 - 21 Jun 2022

Cited by 14 | Viewed by 2559

Abstract

Pancreatic cancer claims over 460,000 victims per year. The carbohydrate antigen (CA) 19-9 test is the blood test used for pancreatic cancer’s detection; however, its levels can be raised in symptomatic patients with other non-malignant diseases, or with other tumors in the surrounding area. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy has demonstrated exceptional potential in cancer diagnostics, and its clinical implementation could represent a significant step towards early detection. This proof-of-concept study, investigating the use of ATR-FTIR spectroscopy on dried blood serum, focused on the discrimination of both cancer versus healthy control samples, and cancer versus symptomatic non-malignant control samples, as a novel liquid biopsy approach for pancreatic cancer diagnosis. Machine learning algorithms were applied, achieving results of up to 92% sensitivity and 88% specificity when discriminating between cancers (n = 100) and healthy controls (n = 100). An area under the curve (AUC) of 0.95 was obtained through receiver operating characteristic (ROC) analysis. Balanced sensitivity and specificity over 75%, with an AUC of 0.83, were achieved with cancers (n = 35) versus symptomatic controls (n = 35). Herein, we present these results as demonstration that our liquid biopsy approach could become a simple, minimally invasive, and reliable diagnostic test for pancreatic cancer detection. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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17 pages, 1579 KiB

Open AccessArticle

Stereotactic Ablative Radiotherapy Using CALYPSO^® Extracranial Tracking for Intrafractional Tumor Motion Management—A New Potential Local Treatment for Unresectable Locally Advanced Pancreatic Cancer? Results from a Retrospective Study

by Hrvoje Kaučić, Domagoj Kosmina, Dragan Schwarz, Andreas Mack, Hrvoje Šobat, Adlan Čehobašić, Vanda Leipold, Iva Andrašek, Asmir Avdičević and Mihaela Mlinarić

Cancers 2022, 14(11), 2688; https://doi.org/10.3390/cancers14112688 - 29 May 2022

Cited by 2 | Viewed by 2168

Abstract

(1) Background: The aim of this study was to evaluate the efficacy and safety of SABR for LAPC using Calypso^® Extracranial Tracking for intrafractional, fiducial-based motion management, to present this motion management technique, as there are yet no published data on usage of Calypso^® during SABR for LAPC, and to report on our clinical outcomes. (2) Methods: Fifty-four patients were treated with SABR in one, three, or five fractions, receiving median BED₁₀ = 112.5 Gy. Thirty-eight patients received systemic treatment. End points were OS, FFLP, PFS, and toxicity. Actuarial survival analysis and univariate analysis were investigated. (3) Results: Median follow-up was 20 months. Median OS was 24 months. One-year FFLP and one-year OS were 100% and 90.7%, respectively. Median PFS was 18 months, and one-year PFS was 72.2%. Twenty-five patients (46.3%) were alive at the time of analysis, and both median FU and OS for this subgroup were 26 months. No acute/late toxicity > G2 was reported. (4) Conclusions: SABR for LAPC using Calypso^® presented as an effective and safe treatment and could be a promising local therapeutic option with very acceptable toxicity, either as a single treatment or in a multimodality regimen. Dose escalation to the tumor combined with systemic treatment could yield better clinical outcomes. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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17 pages, 2028 KiB

Open AccessArticle

Tumour Size and T-Stage in Pancreatic Cancer Resection Specimens Depend on the Pathology Examination Approach

by My Linh Tran, Maia Blomhoff Holm and Caroline Sophie Verbeke

Cancers 2022, 14(10), 2471; https://doi.org/10.3390/cancers14102471 - 17 May 2022

Cited by 1 | Viewed by 2163

Abstract

In the eighth edition of the TNM classification for pancreatic ductal adenocarcinoma (PDAC), stages T1 to T3 are defined by tumour size, size measurement being deemed objective and accurate. This study investigated whether various, currently used approaches to tumour measurement result in different tumour sizes and differences in T-stage assignment. In a series of 315 resected PDAC, tumour sizes were measured as follows: macroscopically in a single or in two perpendicular planes and with or without microscopic corroboration. Comparison of the resulting tumour sizes showed that both macroscopic measurement in two planes and microscopic corroboration gave significantly different results (p < 0.001). Compared to the most simple approach (macroscopic measurement in one plane), the comprehensive approach (macroscopic measurement in two planes with microscopic corroboration) resulted in a larger tumour size in 263 (83%) cases (mean absolute size difference: 10 mm; mean relative size change: 36%). T-stage assignment differed in 142 (45%) cases between the simple and comprehensive approach and affected 87%, 38% and 48% of the cases deemed to be stage T1, T2 and T3, respectively. In conclusion, tumour size and T-stage are highly approach-dependent. Consensus on an accurate method is required to ensure comparability of these basic data. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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Review

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16 pages, 2381 KiB

Open AccessReview

Imaging Modalities for Early Detection of Pancreatic Cancer: Current State and Future Research Opportunities

by Katherina P. Farr, Daniel Moses, Koroush S. Haghighi, Phoebe A. Phillips, Claudia M. Hillenbrand and Boon H. Chua

Cancers 2022, 14(10), 2539; https://doi.org/10.3390/cancers14102539 - 21 May 2022

Cited by 7 | Viewed by 5016

Abstract

Pancreatic cancer, one of the most lethal malignancies, is increasing in incidence. While survival rates for many cancers have improved dramatically over the last 20 years, people with pancreatic cancer have persistently poor outcomes. Potential cure for pancreatic cancer involves surgical resection and adjuvant therapy. However, approximately 85% of patients diagnosed with pancreatic cancer are not suitable for potentially curative therapy due to locally advanced or metastatic disease stage. Because of this stark survival contrast, any improvement in early detection would likely significantly improve survival of patients with pancreatic cancer through earlier intervention. This comprehensive scoping review describes the current evidence on groups at high risk for developing pancreatic cancer, including individuals with inherited predisposition, pancreatic cystic lesions, diabetes, and pancreatitis. We review the current roles of imaging modalities focusing on early detection of pancreatic cancer. Additionally, we propose the use of advanced imaging modalities to identify early, potentially curable pancreatic cancer in high-risk cohorts. We discuss innovative imaging techniques for early detection of pancreatic cancer, but its widespread application requires further investigation and potentially a combination with other non-invasive biomarkers. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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27 pages, 16444 KiB

Open AccessReview

The Role of Endoscopic Ultrasonography in the Diagnosis and Staging of Pancreatic Cancer

by Ali Zakaria, Bayan Al-Share, Jason B. Klapman and Aamir Dam

Cancers 2022, 14(6), 1373; https://doi.org/10.3390/cancers14061373 - 08 Mar 2022

Cited by 9 | Viewed by 3447

Abstract

Pancreatic cancer is the fourth leading cause of cancer-related death and the second gastrointestinal cancer-related death in the United States. Early detection and accurate diagnosis and staging of pancreatic cancer are paramount in guiding treatment plans, as surgical resection can provide the only potential cure for this disease. The overall prognosis of pancreatic cancer is poor even in patients with resectable disease. The 5-year survival after surgical resection is ~10% in node-positive disease compared to ~30% in node-negative disease. The advancement of imaging studies and the multidisciplinary approach involving radiologists, gastroenterologists, advanced endoscopists, medical, radiation, and surgical oncologists have a major impact on the management of pancreatic cancer. Endoscopic ultrasonography is essential in the diagnosis by obtaining tissue (FNA or FNB) and in the loco-regional staging of the disease. The advancement in EUS techniques has made this modality a critical adjunct in the management process of pancreatic cancer. In this review article, we provide an overall description of the role of endoscopic ultrasonography in the diagnosis and staging of pancreatic cancer. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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25 pages, 1132 KiB

Open AccessReview

Evaluating Pancreatic and Biliary Neoplasms with Small Biopsy-Based Next Generation Sequencing (NGS): Doing More with Less

by Ilias P. Nikas, Giannis Mountzios, Guy I. Sydney, Kalliopi J. Ioakim, Jae-Kyung Won and Panagiotis Papageorgis

Cancers 2022, 14(2), 397; https://doi.org/10.3390/cancers14020397 - 13 Jan 2022

Cited by 11 | Viewed by 4036

Abstract

Pancreatic cancer and cholangiocarcinoma are lethal diseases mainly diagnosed at an inoperable stage. As pancreatobiliary surgical specimens are often unavailable for further molecular testing, this review aimed to highlight the diagnostic, prognostic, and therapeutic impact of next-generation sequencing (NGS) performed on distinct small biopsies, including endoscopic ultrasound fine-needle aspirations and biopsies of pancreatic solid and cystic lesions, biliary duct brushings, and also “liquid biopsies” such as the pancreatic juice, bile, and blood. NGS could clarify indeterminate pancreatic lesions or biliary strictures, for instance by identifying TP53 or SMAD4 mutations indicating high-grade dysplasia or cancer. It could also stratify pancreatic cystic lesions, by distinguishing mucinous from non-mucinous cysts and identifying high-risk cysts that should be excised in surgically fit patients, whereas the combination of cytology, elevated cystic CEA levels and NGS could improve the overall diagnostic accuracy. When NGS is performed on the pancreatic juice, it could stratify high-risk patients under surveillance. On the plasma, it could dynamically monitor the disease course and response to therapy. Notably, the circulating tumor DNA (ctDNA) levels have been associated with staging, grading, and survival. Lastly, NGS has shown potential in identifying potentially actionable molecular alterations. In conclusion, NGS applied on small biopsies could carry significant diagnostic, prognostic, and therapeutic value. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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Other

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20 pages, 3405 KiB

Open AccessSystematic Review

Risk Factors for Pancreatic Cancer in Patients with New-Onset Diabetes: A Systematic Review and Meta-Analysis

by Claudia Mellenthin, Vasile Daniel Balaban, Ana Dugic and Stephane Cullati

Cancers 2022, 14(19), 4684; https://doi.org/10.3390/cancers14194684 - 26 Sep 2022

Cited by 8 | Viewed by 3597

Abstract

(1) Background: Patients with new-onset diabetes (NOD) are at risk of pancreatic ductal adenocarcinoma (PDAC), but the most relevant additional risk factors and clinical characteristics are not well established. (2) Objectives: To compare the risk for PDAC in NOD patients to persons without diabetes. Identify risk factors of PDAC among NOD patients. (3) Methods: Medline, Embase, and Google Scholar were last searched in June 2022 for observational studies on NOD patients and assessing risk factors for developing PDAC. Data were extracted, and Meta-Analysis was performed. Pooled effect sizes with 95% confidence intervals (CI) were estimated with DerSimonian & Laird random effects models. (4) Findings: Twenty-two studies were included, and 576,210 patients with NOD contributed to the analysis, of which 3560 had PDAC. PDAC cases were older than controls by 6.14 years (CI 3.64–8.65, 11 studies). The highest risk of PDAC involved a family history of PDAC (3.78, CI 2.03–7.05, 4 studies), pancreatitis (5.66, CI 2.75–11.66, 9 studies), cholecystitis (2.5, CI 1.4–4.45, 4 studies), weight loss (2.49, CI 1.47–4.22, 4 studies), and high/rapidly increasing glycemia (2.33, CI 1.85–2.95, 4 studies) leading to more insulin use (4.91, CI 1.62–14.86, 5 studies). Smoking (ES 1.20, CI 1.03–1.41, 9 studies) and alcohol (ES 1.23, CI 1.09–1.38, 9 studies) have a smaller effect. (5) Conclusion: Important risk factors for PDAC among NOD patients are age, family history, and gallstones/pancreatitis. Symptoms are weight loss and rapid increase in glycemia. The identified risk factors could be used to develop a diagnostic model to screen NOD patients. Full article

(This article belongs to the Special Issue Advances in Diagnosis and Treatment of Pancreatic Cancer)

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