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Frontiers in Pancreatic Cancer

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

Deadline for manuscript submissions: closed (20 June 2022) | Viewed by 29713

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Dr. Amit Mahipal

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Department of Oncology, Mayo Clinic, Rochester, MN, USA
Interests: biliary tract cancers; cholangiocarcinoma; hepatocellular cancer; pancreatic cancer; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic adenocarcinoma is an aggressive malignancy associated with poor prognosis and is the fourth most common cause of cancer death in the United States. Surgery is the only curative option; however, only 20%–30% present at resectable disease at initial diagnosis. There has been advancement in the understanding of pancreatic carcinogenesis and the development of novel therapeutic agents, including chemotherapy and targeted therapies. Neoadjuvant therapy is being increasingly utilized for treatment of pancreatic cancer for better selection of patients undergoing resection.

The objectives of the current Special Issue of Cancers is to highlight both original articles and reviews addressing the current management strategies of pancreatic cancer, including surgery, radiation therapy and systemic therapies. The current issue will include recent advancements in the understanding of the origin and progression of pancreatic cancer and development of novel chemotherapeutic, immunotherapeutic and targeted therapeutic agents.

Dr. Amit Mahipal
Guest Editor

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Published Papers (12 papers)

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Research

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14 pages, 304 KiB

Open AccessArticle

Risk Factors Associated with Pancreatic Cancer in the UK Biobank Cohort

by Te-Min Ke, Artitaya Lophatananon and Kenneth R. Muir

Cancers 2022, 14(20), 4991; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14204991 - 12 Oct 2022

Cited by 4 | Viewed by 1671

Abstract

Evidence on pancreatic cancer (PaCa) risk factors from large population-based cohort studies is limited. This study investigated the PaCa risk factors and the population attributable fraction (PAF) of modifiable risk factors in the UK Biobank cohort. The UK Biobank is a prospective cohort consisting of 502,413 participants with a mean follow-up time of 8.2 years. A binomial generalized linear regression model was used to calculate relative risks for PaCa risk factors. PAF was calculated to estimate the proportional reduction in PaCa if modifiable risk factors were to be eliminated. A total of 728 (0.14%) PaCa incident cases and 412,922 (82.19%) non-PaCa controls were analyzed. The non-modifiable risk factors included age and gender. The modifiable risk factors were cigarette smoking, overweight and obesity, increased waist circumstance, abdominal obesity, Diabetic Mellitus (DM), and pancreatitis history. The PAF suggested that eliminating smoking and obesity can contribute around a 16% reduction in PaCa cases while avoiding abdominal obesity can eliminate PaCa cases by 22%. Preventing pancreatitis and DM could potentially reduce PaCa cases by 1% and 6%, respectively. This study has identified modifiable and non-modifiable PaCa risk factors in the UK population. The PAF of modifiable risk factors can be applied to inform PaCa prevention programs. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

23 pages, 25489 KiB

Open AccessArticle

Hemodynamic, Surgical and Oncological Outcomes of 40 Distal Pancreatectomies with Celiac and Left Gastric Arteries Resection (DP CAR) without Arterial Reconstructions and Preoperative Embolization

by Viacheslav Egorov, Pavel Kim, Alexander Kharazov, Soslan Dzigasov, Pavel Popov, Sofia Rykova, Pavel Zelter, Anna Demidova, Eugeny Kondratiev, Maxim Grigorievsky and Alexander Sorokin

Cancers 2022, 14(5), 1254; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051254 - 28 Feb 2022

Cited by 7 | Viewed by 2182

Abstract

DPCAR’s short- and long-term outcomes are highly diverse, while the causes and prevention of ischemic complications are unclear. To assess oncological, surgical, and hemodynamic outcomes of 40 consecutive DPCARs for pancreatic (n37) and gastric tumors (n3) (2009–2021), retrospective analyses of mortality, morbidity, survival, and hemodynamic consequences after DPCAR were undertaken using case history data, IOUS, and pre- and postoperative CT measurements. In postoperative complications (42.5%), the pancreatic fistula was the most frequent event (27%), 90-day mortality was 7.5. With 27 months median follow-up, median overall (OS) and progression-free survival (PFS) for PDAC were 29 and 18 months, respectively; with 1-, 3-, and 5-years, the OS were 90, 60, and 28%, with an R0-resection rate of 92.5%. Liver and gastric ischemia developed in 0 and 5 (12.5%) cases. Comparison of clinical and vascular geometry data revealed fast adaptation of collateral circulation, insignificant changes in proper hepatic artery diameter, and high risk of ischemic gastropathy if the preoperative diameter of pancreaticoduodenal artery was <2 mm. DP CAR can be performed with acceptable morbidity and survival. OS and RFS in this super-selective cohort were compared to those for resectable cancer. The changes in the postoperative arterial geometry could explain the causes of ischemic complications and determine directions for their prevention. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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13 pages, 938 KiB

Open AccessArticle

Stereotactic Body Radiation Therapy versus Concurrent Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Propensity Score-Matched Analysis

by Young Seob Shin, Hee Hyun Park, Jin-hong Park, Dong-Wan Seo, Sang Soo Lee, Changhoon Yoo, Seonok Kim, Sang Min Yoon, Jinhong Jung, Myung-Hwan Kim, Sung Koo Lee, Do Hyun Park, Tae Jun Song, Dongwook Oh, Baek-Yeol Ryoo, Heung-Moon Chang, Kyu-pyo Kim, Jae Ho Jeong and Jong Hoon Kim

Cancers 2022, 14(5), 1166; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051166 - 24 Feb 2022

Cited by 3 | Viewed by 1897

Abstract

In locally advanced pancreatic cancer (LAPC), stereotactic body radiation therapy (SBRT) has been applied as an alternative to concurrent chemoradiotherapy (CCRT); however, direct comparative evidence between these two modalities is scarce. The aim of this study was to compare the clinical outcomes of SBRT with CCRT for LAPC. We retrospectively reviewed the medical records of patients with LAPC who received SBRT (n = 95) or CCRT (n = 66) with a concurrent 5-FU-based regimen between January 2008 and July 2016. The clinical outcomes of freedom from local progression (FFLP), progression-free survival (PFS), overall survival (OS), and toxicities were analyzed before and after propensity score (PS) matching. After a median follow-up duration of 15.5 months (range, 2.3–64.5), the median OS, PFS, and FFLP of the unmatched patients were 17.3 months, 11 months, and 19.6 months, respectively. After PS matching, there were no significant differences between the SBRT and CCRT groups in terms of the 1-year rates of OS (66.7% vs. 80%, p = 0.455), PFS (40.0% vs. 54.2%, p = 0.123), and FFLP (77.2% and 87.1%, p = 0.691). Our results suggest SBRT could be a feasible alternative to CCRT in treating patients with LAPC. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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12 pages, 29496 KiB

Open AccessArticle

Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma

by Fiona Speichinger, Mihnea P. Dragomir, Simon Schallenberg, Florian N. Loch, Claudius E. Degro, Ann-Kathrin Baukloh, Lisa Hartmann, Ioannis Pozios, Christian Schineis, Georgios Antonios Margonis, Johannes C. Lauscher, Katharina Beyer and Carsten Kamphues

Cancers 2022, 14(1), 201; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010201 - 31 Dec 2021

Cited by 5 | Viewed by 2351

Abstract

Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis, n = 37) and Nc (p = 0.134), while Nm had worse OS than N0 (p < 0.001). Direct invasion alone had no statistically significant effect on OS (p = 0.885). Redefining the N0 stage by including Nc patients showed a more precise OS prediction among N stages (p = 0.001 vs. p = 0.002). Nc was more similar to N0 than to Nm; hence, we suggest a rethinking of TNM classification based on the mechanisms of lymph node metastases in PDAC. Overall, this novel classification is more precise. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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18 pages, 824 KiB

Open AccessArticle

The Costs of Complications and Unplanned Readmissions after Pancreatoduodenectomy for Pancreatic and Periampullary Tumors: Results from a Single Academic Center

by Ralph J. A. Linnemann, Bob J. L. Kooijman, Christian S. van der Hilst, Joost Sprakel, Carlijn I. Buis, Schelto Kruijff and Joost M. Klaase

Cancers 2021, 13(24), 6271; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246271 - 14 Dec 2021

Cited by 5 | Viewed by 1971

Abstract

Background/Objectives: Complications after pancreatoduodenectomy (PD) lead to unplanned readmissions (UR), with a two- to threefold increase in admission costs. In this study, we aimed to create an understanding of the costs of complications and UR in this patient group. Furthermore, we aimed to generate a detailed cost overview that can be used to build a theoretical model to calculate the cost efficacy for prehabilitation. Methods: A retrospective cohort analysis was performed using the Dutch Pancreatic Cancer Audit (DPCA) database of patients who underwent a PD at our institute between 2013 and 2017. The total costs of the index hospital admission and UR related to the PD were collected. Results: Of the 160 patients; 35 patients (22%) had an uncomplicated course; 87 patients (54%) had minor complications, and 38 patients (24%) had severe complications. Median costs for an uncomplicated course were EUR 25.682, and for a complicated course, EUR 32.958 (p = 0.001). The median costs for minor complications were EUR 30.316, and for major complications, EUR 42.664 (p = 0.001). Costs were related to the Comprehensive Complication Index (CCI). The median costs of patients with one or more UR were EUR 41.199. Conclusions: Complications after PD led to a EUR 4.634–EUR 16.982 (18–66%) increase in hospital costs. A UR led to a cost increase of EUR 12.567 (44%). Since hospital costs are directly related to the CCI, reduction in complications will lead to cost-effectiveness. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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Review

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12 pages, 837 KiB

Open AccessReview

Adipose Tissue Wasting as a Determinant of Pancreatic Cancer-Related Cachexia

by Seok-Yeong Yu, Yi Luan, Rosemary Dong, Amirhossein Abazarikia and So-Youn Kim

Cancers 2022, 14(19), 4754; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194754 - 29 Sep 2022

Cited by 2 | Viewed by 2777

Abstract

Pancreatic cancer (PC) is the third leading cause of cancer-related death in the US, and its 5-year survival rate is approximately 10%. The low survival rates largely stem from diagnostic delay and the presence of significant adipose tissue and muscle wasting, commonly referred to as cachexia. Cachexia is present in nearly 80% of PC patients and is a key cause of poor response to treatment and about 20% of death in PC patients. However, there are few clinical interventions proven to be effective against PC-related cachexia. Different cancer types feature distinct secretome profiles and functional characteristics which would lead to cachexia development differently. Therefore, here we discuss affected tissues and potential mechanisms leading to cachexia in PC. We postulate that the most affected tissue during the development of PC-related cachexia is adipose tissue, historically and still thought to be just an inert repository for excess energy in relation to cancer-related cachexia. Adipose tissue loss is considerably greater than muscle loss in quantity and shows a correlation with poor survival in PC patients. Moreover, we suggest that PC mediates adipose atrophy by accelerating adipocyte lipid turnover and fibroblast infiltration. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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19 pages, 713 KiB

Open AccessReview

3D In Vivo Models for Translational Research on Pancreatic Cancer: The Chorioallantoic Membrane (CAM) Model

by Eric Pion, Julia Karnosky, Sofie Boscheck, Benedikt J. Wagner, Katharina M. Schmidt, Stefan M. Brunner, Hans J. Schlitt, Thiha Aung, Christina Hackl and Silke Haerteis

Cancers 2022, 14(15), 3733; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153733 - 31 Jul 2022

Cited by 3 | Viewed by 2411

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with adverse outcomes that have barely improved over the last decade. About half of all patients present with metastasis at the time of diagnosis, and the 5-year overall survival rate across all stages is only 6%. Innovative in vivo research models are necessary to combat this cancer and to discover novel treatment strategies. The chorioallantoic membrane (CAM) model represents one 3D in vivo methodology that has been used in a large number of studies on different cancer types for over a century. This model is based on a membrane formed within fertilized chicken eggs that contain a dense network of blood vessels. Because of its high cost-efficiency, simplicity, and versatility, the CAM model appears to be a highly valuable research tool in the pursuit of gaining more in-depth insights into PDAC. A summary of the current literature on the usage of the CAM model for the investigation of PDAC was conducted and subdivided into angiogenesis, drug testing, modifications, personalized medicine, and further developments. On this comprehensive basis, further research should be conducted on PDAC in order to improve the abysmal prognosis of this malignant disease. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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25 pages, 1411 KiB

Open AccessReview

The Next Frontier in Pancreatic Cancer: Targeting the Tumor Immune Milieu and Molecular Pathways

by Chao Yin, Ali Alqahtani and Marcus S. Noel

Cancers 2022, 14(11), 2619; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112619 - 25 May 2022

Cited by 7 | Viewed by 2597

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with abysmal prognosis. It is currently the third most common cause of cancer-related mortality, despite being the 11th most common cancer. Chemotherapy is standard of care in all stages of pancreatic cancer, yet survival, particularly in the advanced stages, often remains under one year. We are turning to immunotherapies and targeted therapies in PDAC in order to directly attack the core features that make PDAC notoriously resistant to chemotherapy. While the initial studies of these agents in PDAC have generally been disappointing, we find optimism in recent preclinical and early clinical research. We find that despite the immunosuppressive effects of the PDAC tumor microenvironment, new strategies, such as combining immune checkpoint inhibitors with vaccine therapy or chemokine receptor antagonists, help elicit strong immune responses. We also expand on principles of DNA homologous recombination repair and highlight opportunities to use agents, such as PARP inhibitors, that exploit deficiencies in DNA repair pathways. Lastly, we describe advances in direct targeting of driver mutations and metabolic pathways and highlight some technological achievements such as novel KRAS inhibitors. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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19 pages, 363 KiB

Open AccessReview

Systemic Therapy of Metastatic Pancreatic Adenocarcinoma: Current Status, Challenges, and Opportunities

by Sakti Chakrabarti, Mandana Kamgar and Amit Mahipal

Cancers 2022, 14(11), 2588; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112588 - 24 May 2022

Cited by 7 | Viewed by 2387

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by nonspecific presenting symptoms, lack of a screening test, rapidly progressive clinical course, and presentation with an advanced-stage disease in the majority of patients. PDAC is essentially a systemic disease irrespective of the initial stage, as most patients with non-metastatic PDAC undergoing curative-intent treatment eventually experience metastatic relapse. Currently, cytotoxic chemotherapy remains the cornerstone of treatment in patients with advanced disease. However, the current standard treatment with multiagent chemotherapy has modest efficacy and results in median overall survival (OS) of less than a year and a 5-year OS of about 10%. The pathobiology of PDAC poses many challenges, including a unique tumor microenvironment interfering with drug delivery, intratumoral heterogeneity, and a strongly immunosuppressive microenvironment that supports cancer growth. Recent research is exploring a wide range of novel therapeutic targets, including genomic alterations, tumor microenvironment, and tumor metabolism. The rapid evolution of tumor genome sequencing technologies paves the way for personalized, targeted therapies. The present review summarizes the current chemotherapeutic treatment paradigm of advanced PDAC and discusses the evolving novel targets that are being investigated in a myriad of clinical trials. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

15 pages, 14878 KiB

Open AccessReview

Microbial Associations with Pancreatic Cancer: A New Frontier in Biomarkers

by Mark Stasiewicz, Marek Kwaśniewski and Tomasz M. Karpiński

Cancers 2021, 13(15), 3784; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153784 - 27 Jul 2021

Cited by 18 | Viewed by 3010

Abstract

Pancreatic cancer (PC) remains a global health concern with high mortality and is expected to increase as a proportion of overall cancer cases in the coming years. Most patients are diagnosed at a late stage of disease progression, which contributes to the extremely low 5-year survival rates. Presently, screening for PC remains costly and time consuming, precluding the use of widespread testing. Biomarkers have been explored as an option by which to ameliorate this situation. The authors conducted a search of available literature on PubMed to present the current state of understanding as it pertains to the use of microbial biomarkers and their associations with PC. Carriage of certain bacteria in the oral cavity (e.g., Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Streptococcus sp.), gut (e.g., Helicobacter pylori, Synergistetes, Proteobacteria), and pancreas (e.g., Fusobacterium sp., Enterobacteriaceae, Pseudomonadaceae) has been associated with an increased risk of developing PC. Additionally, the fungal genus Malassezia has likewise been associated with PC development. This review further outlines potential oncogenic mechanisms involved in the microbial-associated development of PC. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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18 pages, 7674 KiB

Open AccessSystematic Review

Prognostic, Diagnostic, and Clinicopathological Significance of Circular RNAs in Pancreatic Cancer: A Systematic Review and Meta-Analysis

by Jiajia Li, Ziping Ye, Xiaolin Hu, Sicong Hou and Qinglei Hang

Cancers 2022, 14(24), 6187; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246187 - 14 Dec 2022

Cited by 6 | Viewed by 1540

Abstract

Pancreatic cancer (PC) is a highly aggressive malignant tumor with a high mortality rate. It is urgent to find optimal molecular targets for the early diagnosis and treatment of PC. Here, we aimed to systematically analyze the prognostic, diagnostic, and clinicopathological significance of circular RNAs (circRNAs) in PC. Relevant studies were screened through PubMed, Web of Science, and other databases. The prognostic value of PC-associated circRNAs was assessed using the composite hazard ratio (HR), the diagnostic performance was assessed using the area under the summary receiver operator characteristic (SROC) curve (AUC), and the correlation with clinicopathological characteristics using the composite odds ratio (OR) was explored. In our study, 48 studies were included: 34 for prognosis, 11 for diagnosis, and 30 for correlation with clinicopathological characteristics. For prognosis, upregulated circRNAs were associated with poorer overall survival (OS) (HR = 2.02) and disease-free survival/progression-free survival (HR = 1.84) while downregulated circRNAs were associated with longer OS (HR = 0.55). Notably, the combination of circRNAs, including hsa_circ_0064288, hsa_circ_0000234, hsa_circ_0004680, hsa_circ_0071036, hsa_circ_0000677, and hsa_circ_0001460, was associated with worse OS (HR = 2.35). For diagnosis, the AUC was 0.83, and the pooled sensitivity and specificity were 0.79 and 0.73, respectively. For clinicopathologic characteristics, upregulated circRNAs were associated with poorer tumor differentiation, more nerve and vascular invasion, higher T stage, lymphatic metastasis, distant metastasis, advanced TNM stage, and higher preoperative CA19-9 level. In contrast, downregulated circRNAs were negatively associated with PC differentiation and lymphatic metastasis. Overall, our results showed that circRNAs are closely related to the prognosis and clinicopathological characteristics of PC patients and could be utilized for early diagnosis; thus, they are promising biomarkers for clinical application in PC. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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17 pages, 1445 KiB

Open AccessSystematic Review

Efficacy and Safety of Neoadjuvant Gemcitabine Plus Nab-Paclitaxel in Borderline Resectable and Locally Advanced Pancreatic Cancer—A Systematic Review and Meta-Analysis

by Marko Damm, Ljupcho Efremov, Benedikt Birnbach, Gretel Terrero, Jörg Kleeff, Rafael Mikolajczyk, Jonas Rosendahl, Patrick Michl and Sebastian Krug

Cancers 2021, 13(17), 4326; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174326 - 27 Aug 2021

Cited by 17 | Viewed by 3127

Abstract

Therapy with gemcitabine and nab-paclitaxel (GNP) is the most commonly used palliative chemotherapy, but its advantage in the neoadjuvant setting remains unclear. Accordingly, our aim is to evaluate the impact of first-line neoadjuvant therapy with GNP in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC). A systematic search for published studies until August 2020 was performed. The primary endpoint included resection and R0 resection rates in the intention-to-treat population. Secondary endpoints were response rate, survival and toxicity. Among 21 studies, 950 patients who received neoadjuvant GNP were evaluated. Treatment with GNP resulted in surgical resection and R0 resection rates as follows: 49% (95% CI 30–68%) and 36% (95% CI 17–58%) for BRPC and 16% (95% CI 7–26%) and 11% (95% CI 5–19%) for LAPC, respectively. The objective response rates and the median overall survival (mOS) ranged from 0 to 67% and 12 to 30 months, respectively. Neutropenia (range 5–77%) and neuropathy (range 0–22%) were the most commonly reported grade 3 to 4 adverse events. Neoadjuvant chemotherapy with GNP can be performed safely and with valuable effects in patients with BRPC and LAPC. The utility of GNP in comparison to FOLFIRINOX in the neoadjuvant setting requires further investigation in prospective randomized trials. Full article

(This article belongs to the Special Issue Frontiers in Pancreatic Cancer)

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