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17 pages, 599 KiB

Open AccessArticle

An Integrative Pancreatic Cancer Risk Prediction Model in the UK Biobank

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

Biomedicines 2023, 11(12), 3206; https://doi.org/10.3390/biomedicines11123206 - 1 Dec 2023

Cited by 2 | Viewed by 2146

Abstract

Pancreatic cancer (PaCa) is a lethal cancer with an increasing incidence, highlighting the need for early prevention strategies. There is a lack of a comprehensive PaCa predictive model derived from large prospective cohorts. Therefore, we have developed an integrated PaCa risk prediction model [...] Read more.

Pancreatic cancer (PaCa) is a lethal cancer with an increasing incidence, highlighting the need for early prevention strategies. There is a lack of a comprehensive PaCa predictive model derived from large prospective cohorts. Therefore, we have developed an integrated PaCa risk prediction model for PaCa using data from the UK Biobank, incorporating lifestyle-related, genetic-related, and medical history-related variables for application in healthcare settings. We used a machine learning-based random forest approach and a traditional multivariable logistic regression method to develop a PaCa predictive model for different purposes. Additionally, we employed dynamic nomograms to visualize the probability of PaCa risk in the prediction model. The top five influential features in the random forest model were age, PRS, pancreatitis, DM, and smoking. The significant risk variables in the logistic regression model included male gender (OR = 1.17), age (OR = 1.10), non-O blood type (OR = 1.29), higher polygenic score (PRS) (Q5 vs. Q1, OR = 2.03), smoking (OR = 1.82), alcohol consumption (OR = 1.27), pancreatitis (OR = 3.99), diabetes (DM) (OR = 2.57), and gallbladder-related disease (OR = 2.07). The area under the receiver operating curve (AUC) of the logistic regression model is 0.78. Internal validation and calibration performed well in both models. Our integrative PaCa risk prediction model with the PRS effectively stratifies individuals at future risk of PaCa, aiding targeted prevention efforts and supporting community-based cancer prevention initiatives. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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12 pages, 1813 KiB

Open AccessArticle

Impact of Portal Vein Resection (PVR) in Patients Who Underwent Curative Intended Pancreatic Head Resection

by Markus Bernhardt, Felix Rühlmann, Azadeh Azizian, Max Alexander Kölling, Tim Beißbarth, Marian Grade, Alexander Otto König, Michael Ghadimi and Jochen Gaedcke

Biomedicines 2023, 11(11), 3025; https://doi.org/10.3390/biomedicines11113025 - 11 Nov 2023

Cited by 2 | Viewed by 1156

Abstract

The oncological impact of portal vein resection (PVR) in pancreatic cancer surgery remains contradictory. Different variables might have an impact on the outcome. The aim of the present study is the retrospective assessment of the frequency of PVR, histological confirmation of tumor infiltration, [...] Read more.

The oncological impact of portal vein resection (PVR) in pancreatic cancer surgery remains contradictory. Different variables might have an impact on the outcome. The aim of the present study is the retrospective assessment of the frequency of PVR, histological confirmation of tumor infiltration, and comparison of oncological outcomes in PVR patients. We retrieved n = 90 patients from a prospectively collected data bank who underwent pancreas surgery between 2012 and 2019 at the University Medical Centre Göttingen (Germany) and showed a histologically confirmed pancreatic ductal adenocarcinoma (PDAC). While 50 patients (55.6%) underwent pancreatic resection combined with PVR, 40 patients (44.4%) received standard pancreatic surgery. Patients with distal pancreatectomy or a tumor other than PDAC were excluded. PVR was performed either as local excision or circular resection of the portal vein. Clinical/patient data and follow-ups were retrieved. The median follow-up period was 20.5 months. Regarding the oncological outcome, a statistically poorer CSS (p = 0.04) was observed in PVR patients. There was no difference (p = 0.18) in patients’ outcomes between tangential and complete PVR, while n = 21 (42% of PVR patients) showed portal vein infiltration. The correlation between performed PVR and resection status was statistically significant: 48.6% of PVR patients achieved R0 resections compared to 75% in non-PVR patients (p = 0.03). Patients who underwent PDAC surgery with PVR show a significantly poorer outcome regardless of PVR type. Tumor size and R-status remain two important variables significantly associated with outcome. Since there is a lack of standardization for the indication of PVR, it remains unknown if the need for resection of vein structures during pancreatic resection represents the biological aggressiveness of the tumor or is biased by the experience of the surgeon. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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16 pages, 17134 KiB

Open AccessArticle

Heme Oxygenase-1 Inhibition Modulates Autophagy and Augments Arsenic Trioxide Cytotoxicity in Pancreatic Cancer Cells

by Iman M. Ahmad, Alicia J. Dafferner, Ramia J. Salloom and Maher Y. Abdalla

Biomedicines 2023, 11(9), 2580; https://doi.org/10.3390/biomedicines11092580 - 20 Sep 2023

Cited by 4 | Viewed by 1676

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that hypoxia and chemotherapy induced expression of Heme Oxygenase-1 (HO-1) in PDAC cells and tissues. Arsenic trioxide (ATO) is [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that hypoxia and chemotherapy induced expression of Heme Oxygenase-1 (HO-1) in PDAC cells and tissues. Arsenic trioxide (ATO) is the first-line chemotherapeutic drug for acute promyelocytic leukemia (APL). ATO increases the generation of reactive oxidative species (ROS) and induces apoptosis in treated cells. The clinical use of ATO for solid tumors is limited due to severe systemic toxicity. In order to reduce cytotoxic side effects and resistance and improve efficacy, it has become increasingly common to use combination therapies to treat cancers. In this study, we used ATO-sensitive and less sensitive PDAC cell lines to test the effect of combining HO-1 inhibitors (SnPP and ZnPP) with ATO on HO-1 expression, cell survival, and other parameters. Our results show that ATO significantly induced the expression of HO-1 in different PDAC cells through the p38 MAPK signaling pathway. ROS production was confirmed using the oxygen-sensitive probes DCFH and DHE, N-acetyl cysteine (NAC), an ROS scavenger, and oxidized glutathione levels (GSSG). Both ATO and HO-1 inhibitors reduced PDAC cell survival. In combined treatment, inhibiting HO-1 significantly increased ATO cytotoxicity, disrupted the GSH cycle, and induced apoptosis as measured using flow cytometry. ATO and HO-1 inhibition modulated autophagy as shown by increased expression of autophagy markers ATG5, p62, and LC3B in PDAC cells. This increase was attenuated by NAC treatment, indicating that autophagy modulation was through an ROS-dependent mechanism. In conclusion, our work explored new strategies that could lead to the development of less toxic and more effective therapies against PDAC by combining increased cellular stress and targeting autophagy. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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14 pages, 3017 KiB

Open AccessArticle

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

by Rafał Pęksa, Michał Kunc, Piotr Czapiewski, Michał Piątek, Stanisław Hać, Barbara Radecka and Wojciech Biernat

Biomedicines 2022, 10(7), 1761; https://doi.org/10.3390/biomedicines10071761 - 21 Jul 2022

Cited by 3 | Viewed by 2441

Abstract

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death in developed countries. Only 15% of patients are candidates for radical surgery, and adequate prognostication may guide proper postsurgical management. We aimed to retrospectively assess the prognostic significance of the immunohistochemical expression [...] Read more.

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death in developed countries. Only 15% of patients are candidates for radical surgery, and adequate prognostication may guide proper postsurgical management. We aimed to retrospectively assess the prognostic significance of the immunohistochemical expression of immune checkpoint receptors (PD-L1 and VISTA), markers of systemic inflammation, thrombosis in the tumor area, and the tumor budding in the group of 107 patients diagnosed with pancreatic adenocarcinoma in a single center. The high expression of PD-L1 on tumor cells (TCs) was associated with worse overall survival (OS, p = 0.041, log-rank). On the contrary, high PD-L1 or VISTA on tumor-associated immune cells (TAICs) was correlated with better OS (p = 0.006 and p = 0.008, respectively, log-rank). The joint status of PD-L1 on TCs and TAICs stratified patients into three prognostic groups. The cases with high-grade budding were characterized by higher PD-L1 expression on TCs (p = 0.008) and elevated systemic inflammatory markers. Moreover, budding was identified as the independent prognostic factor in multivariate Cox regression analysis (HR = 2.87; 95% CI = 1.75–4.68; p < 0.001). To conclude, the pattern of PD-L1 and VISTA expression was associated with survival in univariate analysis. Tumor budding accurately predicts outcomes in pancreatic cancer and should be incorporated into routine histopathological practice. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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11 pages, 2191 KiB

Open AccessArticle

Isolated Gastric Metastases of Pancreatic Ductal Adenocarcinoma following Radical Resection—Impact of Endosonography-Guided Fine Needle Aspiration Tract Seeding

by Martin Loveček, Pavel Skalický, Ondřej Urban, Jana Tesaříková, Martin Kliment, Róbert Psár, Hana Švébišová, Kateřina Urban, Beatrice Mohelníková-Duchoňová, Dušan Klos and Martin Stašek

Biomedicines 2022, 10(6), 1392; https://doi.org/10.3390/biomedicines10061392 - 12 Jun 2022

Cited by 2 | Viewed by 2132

Abstract

Background: Endosonography-guided fine needle aspiration biopsy (EUS-FNA)-associated metachronous gastric seeding metastases (GSM) of pancreatic ductal adenocarcinoma (PDAC) represent a serious condition with insufficient evidence. Methods: Retrospective analysis of PDAC resections with a curative-intent, proven pathological diagnosis of PDAC, preoperative EUS-FNA and post-resection follow-up [...] Read more.

Background: Endosonography-guided fine needle aspiration biopsy (EUS-FNA)-associated metachronous gastric seeding metastases (GSM) of pancreatic ductal adenocarcinoma (PDAC) represent a serious condition with insufficient evidence. Methods: Retrospective analysis of PDAC resections with a curative-intent, proven pathological diagnosis of PDAC, preoperative EUS-FNA and post-resection follow-up of at least 60 months. The systematic literature search of published data was used for the GSM growth evaluation using Pearson correlation and the linear regression analyses. Results: The inclusion criteria met 59/134 cases, 16 (27%) had retained needle tract (15 following distal pancreatectomy, 1 following pylorus-sparing head resection). In total, 3/16 cases (19%) developed identical solitary GSM (10–26th month following primary surgery) and were radically resected. A total of 30 published cases of PDAC GSM following EUS-FNA were identified. Lesion was resected in 20 distal pancreatectomy cases with complete information in 14 cases. A correlation between the metastasis size and time (r = 0.612) was proven. The regression coefficient b = 0.72 expresses the growth of 0.72 mm per month. Conclusions: The GSM represent a preventable and curable condition. A remarkably high number of GSM following EUS-FNA was identified, leading to follow-up recommendation of EUS-FNA sampled patients. Multimodal management (gastric resection, adjuvant chemotherapy) may prolong survival. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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16 pages, 2035 KiB

Open AccessArticle

Impact of Endoluminal Radiofrequency Ablation on Immunity in Pancreatic Cancer and Cholangiocarcinoma

by Jana Jarosova, Peter Macinga, Lenka Krupickova, Martina Fialova, Alzbeta Hujova, Jan Mares, Ondrej Urban, Jan Hajer, Julius Spicak, Ilja Striz and Tomas Hucl

Biomedicines 2022, 10(6), 1331; https://doi.org/10.3390/biomedicines10061331 - 6 Jun 2022

Cited by 10 | Viewed by 3082

Abstract

Radiofrequency ablation (RFA) is a mini-invasive loco-regional ablation technique that is increasingly being used as a palliative treatment for pancreatic cancer and cholangiocarcinoma. Ablation-triggered immune system stimulation has been proposed as a mechanism behind the systemic effects of RFA. The aim of our [...] Read more.

Radiofrequency ablation (RFA) is a mini-invasive loco-regional ablation technique that is increasingly being used as a palliative treatment for pancreatic cancer and cholangiocarcinoma. Ablation-triggered immune system stimulation has been proposed as a mechanism behind the systemic effects of RFA. The aim of our study was to investigate the immune response to endoluminal biliary RFA. Peripheral blood samples were collected from patients with pancreatic cancer and cholangiocarcinoma randomised to receive endoluminal biliary radiofrequency ablation + stent (19 patients) or stent only (21 patients). We observed an early increase in IL-6 levels and a delayed increase in CXCL1, CXCL5, and CXCL11 levels as well as an increase in CD8+ and NK cells. However, these changes were not specific to RFA treatment. Explicitly in response to RFA, we observed a delayed increase in serum CXCL1 levels and an early decrease in the number of anti-inflammatory CD206+ blood monocytes. Our study provides the first evidence of endoluminal biliary RFA-based regulation of the systemic immune response in patients with pancreatic cancer and cholangiocarcinoma. These changes were characterised by a general inflammatory response. RFA-specific activation of the adaptive immune system was not confirmed. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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Review

Jump to: Research

12 pages, 2939 KiB

Open AccessReview

Principles of Palliative and Supportive Care in Pancreatic Cancer: A Review

by Robert Mazur and Jan Trna

Biomedicines 2023, 11(10), 2690; https://doi.org/10.3390/biomedicines11102690 - 1 Oct 2023

Cited by 5 | Viewed by 2455

Abstract

Pancreatic adenocarcinoma (PDAC) is well known for its poor survival time. Clinical symptoms are painless jaundice or abdominal or back pain. Less specific symptoms often appear that make diagnosis difficult, e.g., weight loss, loss of appetite, nausea and vomiting, and general weakness. Only [...] Read more.

Pancreatic adenocarcinoma (PDAC) is well known for its poor survival time. Clinical symptoms are painless jaundice or abdominal or back pain. Less specific symptoms often appear that make diagnosis difficult, e.g., weight loss, loss of appetite, nausea and vomiting, and general weakness. Only 10–20% of patients are diagnosed at an early stage. A cure is practically only possible with a radical surgical operation. In the case of locally advanced findings, neoadjuvant therapy is administered. Among the therapeutic options offered are chemotherapy, radiotherapy (including stereotactic radiotherapy—SBRT), targeted treatment, or immunotherapy. In the case of metastatic disease, of which more than half are present at diagnosis, the goal is to relieve the patient of problems. Metastatic PDAC can cause problems arising from the localization of distant metastases, but it also locally affects the organs it infiltrates. In our review article, we focus on the largest group of patients, those with locally advanced disease and metastatic disease—symptoms related to the infiltration or destruction of the pancreatic parenchyma and the growth of the tumor into the surrounding. Therefore, we deal with biliary or duodenal obstruction, gastric outlet syndrome, bleeding and thromboembolic diseases, pain, depression, and fatigue, as well as pancreatic exocrine insufficiency and malnutrition. Metastatic spread is most often to the liver, peritoneum, or lungs. The presented overview aims to offer current therapeutic options across disciplines. In accordance with modern oncology, a multidisciplinary approach with a procedure tailored to the specific patient remains the gold standard. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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23 pages, 5414 KiB

Open AccessReview

Stereotactic Body Radiotherapy (SBRT) of Pancreatic Cancer—A Critical Review and Practical Consideration

by Petr Burkoň, Jan Trna, Marek Slávik, Radim Němeček, Tomáš Kazda, Petr Pospíšil, Milan Dastych, Michal Eid, Ivo Novotný, Tomáš Procházka and Miroslav Vrzal

Biomedicines 2022, 10(10), 2480; https://doi.org/10.3390/biomedicines10102480 - 4 Oct 2022

Cited by 9 | Viewed by 3880

Abstract

Pancreatic cancer is the third leading cause of cancer death in the developed world and is predicted to become the second by 2030. A cure may be achieved only with surgical resection of an early diagnosed disease. Surgery for more advanced disease is [...] Read more.

Pancreatic cancer is the third leading cause of cancer death in the developed world and is predicted to become the second by 2030. A cure may be achieved only with surgical resection of an early diagnosed disease. Surgery for more advanced disease is challenging and can be contraindicated for many reasons. Neoadjuvant therapy may improve the probability of achieving R0 resection. It consists of systemic treatment followed by radiation therapy applied concurrently or sequentially with cytostatics. A novel approach to irradiation, stereotactic body radiotherapy (SBRT), has the potential to improve treatment results. SBRT can deliver higher doses of radiation to the tumor in only a few treatment fractions. It has attracted significant interest for pancreatic cancer patients, as it is completed quickly, requires less time away from full-dose chemotherapy, and is well-tolerated than conventional radiotherapy. In this review, we aim to provide the reader with a basic overview of current evidence for SBRT indications in the treatment of pancreatic tumors. In the second part of the review, we focus on practical information with respect to SBRT treatment plan preparation the performance of such therapy. Finally, we discuss future directions related to the use of magnetic resonance linear accelerators. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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16 pages, 3801 KiB

Open AccessReview

Current Screening Strategies for Pancreatic Cancer

by Petr Vanek, Ondrej Urban, Vincent Zoundjiekpon and Premysl Falt

Biomedicines 2022, 10(9), 2056; https://doi.org/10.3390/biomedicines10092056 - 23 Aug 2022

Cited by 9 | Viewed by 2737

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a dreaded malignancy with a dismal 5-year survival rate despite maximal efforts on optimizing treatment strategies. Radical surgery is the only potential curative procedure. Unfortunately, the majority of patients are diagnosed with locally advanced or metastatic disease, which [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a dreaded malignancy with a dismal 5-year survival rate despite maximal efforts on optimizing treatment strategies. Radical surgery is the only potential curative procedure. Unfortunately, the majority of patients are diagnosed with locally advanced or metastatic disease, which renders them ineligible for curative resection. Early detection of PDAC is thus considered to be the most effective way to improve survival. In this regard, pancreatic screening has been proposed to improve results by detecting asymptomatic stages of PDAC and its precursors. There is now evidence of benefits of systematic surveillance in high-risk individuals, and the current guidelines emphasize the potential of screening to affect overall survival in individuals with genetic susceptibility syndromes or familial occurrence of PDAC. Here we aim to summarize the current knowledge about screening strategies for PDAC, including the latest epidemiological data, risk factors, associated hereditary syndromes, available screening modalities, benefits, limitations, as well as management implications. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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14 pages, 324 KiB

Open AccessReview

Intraductal Papillary Mucinous Neoplasms in Hereditary Cancer Syndromes

by Devarshi R. Ardeshna, Shiva Rangwani, Troy Cao, Timothy M. Pawlik, Peter P. Stanich and Somashekar G. Krishna

Biomedicines 2022, 10(7), 1475; https://doi.org/10.3390/biomedicines10071475 - 22 Jun 2022

Cited by 14 | Viewed by 3387

Abstract

Hereditary pancreatic cancer, which includes patients with familial pancreatic cancer (FPC) and hereditary pancreatic cancer syndromes, accounts for about 10% of all pancreatic cancer diagnoses. The early detection of pre-cancerous pancreatic cysts has increasingly become a focus of interest in recent years as [...] Read more.

Hereditary pancreatic cancer, which includes patients with familial pancreatic cancer (FPC) and hereditary pancreatic cancer syndromes, accounts for about 10% of all pancreatic cancer diagnoses. The early detection of pre-cancerous pancreatic cysts has increasingly become a focus of interest in recent years as a potential avenue to lower pancreatic cancer incidence and mortality. Intraductal papillary mucinous cystic neoplasms (IPMNs) are recognized precursor lesions of pancreatic cancer. IPMNs have high prevalence in patients with hereditary pancreatic cancer and their relatives. While various somatic mutations have been identified in IPMNs, certain germline mutations associated with hereditary cancer syndromes have also been identified in IPMNs, suggesting a role in their formation. While the significance for the higher prevalence of IPMNs or similar germline mutations in these high-risk patients remain unclear, IPMNs do represent pre-malignant lesions that need close surveillance. This review summarizes the available literature on the incidence and prevalence of IPMNs in inherited genetic predisposition syndromes and FPC and speculates if IPMN and pancreatic cancer surveillance in these high-risk individuals needs to change. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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