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Sato R, Hotta K, Kubo T, Horiguchi S, Kato H, Matsumoto K, Kozuki T, Udono H, Kiura K, Otsuka M. Durable Response to Nivolumab Combined With Metformin in Advanced Pancreatic Cancer: A Case Report With Seven Years of Follow-Up. Cureus 2025; 17:e79001. [PMID: 40092004 PMCID: PMC11910964 DOI: 10.7759/cureus.79001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
We report a case of poorly differentiated pancreatic cancer that showed an exceptional response to combination therapy with nivolumab and metformin. A 58-year-old man presented with epigastric pain and was diagnosed with locally advanced pancreatic cancer with para-aortic lymph node metastasis. After disease progression following modified FOLFIRINOX therapy (a combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin), the patient was enrolled in a phase Ib clinical trial of nivolumab (3 mg/kg biweekly) combined with metformin (750 mg/day). Post-treatment imaging showed marked tumor shrinkage with normalization of the tumor markers. During treatment, the patient was diagnosed with early-stage lung cancer and underwent successful left S1+S2 segmentectomy with temporary suspension of immunotherapy. The therapeutic response of pancreatic cancer has been sustained for seven years, with minimal residual disease. This unprecedented response duration is particularly noteworthy considering his microsatellite stability, which typically predicts a limited response to immune checkpoint inhibition. This case demonstrates an exceptional response to nivolumab and metformin combination therapy in poorly differentiated pancreatic cancer. The remarkable durability of the response suggests the need for further investigation to identify patients most likely to benefit from this therapeutic approach.
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Affiliation(s)
- Ryosuke Sato
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, JPN
| | - Katsuyuki Hotta
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, JPN
| | - Toshio Kubo
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, JPN
| | - Shigeru Horiguchi
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, JPN
| | - Hironari Kato
- Department of Gastroenterology, Okayama City Hospital, Okayama, JPN
| | - Kazuyuki Matsumoto
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, JPN
| | - Toshiyuki Kozuki
- Department of Respiratory Medicine and Allergology, Kochi Medical School, Kochi University, Kochi, JPN
| | - Heiichiro Udono
- Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JPN
| | - Katsuyuki Kiura
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, JPN
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, JPN
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Aseafan M, Alfakeeh AH, Tashkandi E, Mahrous M, Alghamdi M, Alshamsan B, Al-Hajeili M, Bakhsh S, Alshammari K, Almugbel FA, Alfagih AH, Allehebi A, Montaser M, Elsafty MH, Elnaghi KAE, Issa I, Bakshi E, AlSubaie S, AlMutairi B, Mokhtar H, Aboelatta M, Bukhari N, Alzahrani AM, Elhassan T, Alqahtani A, Bazarbashi S. Real-world clinical outcome of unresectable locally advanced & de-novo metastatic pancreatic ductal adenocarcinoma: a multicentre retrospective study. BMC Cancer 2025; 25:7. [PMID: 39754118 PMCID: PMC11697791 DOI: 10.1186/s12885-024-13386-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 12/23/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited treatment options yielding poor outcomes. This study aimed to evaluate the real-world clinical characteristics, treatment patterns, and outcomes of patients with locally advanced unresectable and de-novo metastatic PDAC in Saudi Arabia, providing regional data to compare with international benchmarks. METHODS This is a retrospective, multicentre study involving 350 patients diagnosed with unresectable locally advanced or de-novo metastatic PDAC between January 2015 and November 2023. Data were collected from 10 oncology centers across Saudi Arabia. RESULTS The median age at diagnosis was 60 years, with 63% of patients presenting with multiple metastatic sites, primarily in the liver (66.3%). FOLFIRINOX was the most common first-line treatment (55.1%), followed by gemcitabine plus nab-paclitaxel (15.1%). The median PFS for first-line treatment was 5.3 months, with FOLFIRINOX achieving the longest PFS (6.5 months). The median OS was 10.34 months for the entire cohort, with better survival outcomes observed in patients receiving FOLFIRINOX (12.3 months). Independent prognostic factors for PFS and OS included performance status, first-line regimen, and neutrophil-lymphocyte ratio (NLR). Among patients tested, 7.1% had deficient mismatch repair (d-MMR), and 5.8% harbored BRCA mutations. CONCLUSIONS This real-world study confirms that clinical outcomes for locally advanced unresectable and metastatic PDAC in Saudi Arabia are consistent with international data, with FOLFIRINOX showing superior outcomes over gemcitabine-based regimens. However, both treatments reflect the persistent poor prognosis of PDAC, underscoring the need for novel therapeutic strategies. Further research is warranted to optimize treatment selection and improve survival outcomes in this population.
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Affiliation(s)
- Mohamed Aseafan
- Section of Medical Oncology, Department of Internal Medicine, Security Forces Hospital, Riyadh, Saudi Arabia.
| | - Ali H Alfakeeh
- Comprehensive Cancer Center, Medical Oncology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Emad Tashkandi
- College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mervat Mahrous
- Department of Oncology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
- Collage of Medicine, Minia University, Minia, Egypt
| | - Mohammed Alghamdi
- Oncology Center, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Bader Alshamsan
- Department of Medicine, College of Medicine, Qassim University, Buraydah, Saudi Arabia
- Prince Faisal Cancer Center, King Fahad Specialist Hospital, Qassim Health Clusster, Buraydah, Saudi Arabia
| | - Marwan Al-Hajeili
- Department of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Safwan Bakhsh
- Department of Medical Oncology, King Faisal Specialist Hospital and Research Center-Jeddah, Jeddah, Saudi Arabia
| | - Kanan Alshammari
- Department of Medical Oncology, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Fahad A Almugbel
- Department of Medical Oncology, Cancer Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdulhameed H Alfagih
- Comprehensive Cancer Center, Medical Oncology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Ahmed Allehebi
- Department of Medical Oncology, King Faisal Specialist Hospital and Research Center-Jeddah, Jeddah, Saudi Arabia
| | - Mohamed Montaser
- Section of Medical Oncology, Department of Internal Medicine, Security Forces Hospital, Riyadh, Saudi Arabia
- Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | | | - Ibrahim Issa
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Eesa Bakshi
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Sadeem AlSubaie
- Pathology and Laboratory Medicine, Security Forces Hospital, Riyadh, Saudi Arabia
| | - Bandar AlMutairi
- Department of Oncology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Hoda Mokhtar
- Department of Oncology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mohamed Aboelatta
- Prince Faisal Cancer Center, King Fahad Specialist Hospital, Qassim Health Clusster, Buraydah, Saudi Arabia
| | - Nedal Bukhari
- Department of Oncology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Ali M Alzahrani
- Comprehensive Cancer Center, Medical Oncology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Tusneem Elhassan
- Research Unit, Cancer Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ali Alqahtani
- Department of Medical Oncology, Cancer Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Shouki Bazarbashi
- Department of Medical Oncology, Cancer Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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Smith LM, Mahoney DW, Bamlet WR, Yu F, Liu S, Goggins MG, Darabi S, Majumder S, Wang QL, Coté GA, Demeure MJ, Zhang Z, Srivastava S, Chawla A, Izmirlian G, Olson JE, Wolpin BM, Genkinger JM, Zaret KS, Brand R, Koay EJ, Oberg AL. Early detection of pancreatic cancer: Study design and analytical considerations in biomarker discovery and early phase validation studies. Pancreatology 2024; 24:1265-1279. [PMID: 39516175 PMCID: PMC11780679 DOI: 10.1016/j.pan.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 10/05/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that is challenging to detect at an early stage. Biomarkers are needed that can detect PDAC early in the course of disease when interventions lead to the best outcomes. We highlight study design and statistical considerations that inform pancreatic cancer early detection biomarker evaluation. METHODS We describe experimental design strategies in this setting useful for streamlining biomarker evaluation at each Early Detection Research Network (EDRN) phase of biomarker development. We break the early EDRN phases into sub-phases, proposing objectives, study design strategies, and biomarker performance benchmarks. RESULTS The goal of early detection in populations at high-risk of PDAC is described. Evaluating biomarker behavior in patients under surveillance without disease can winnow candidate biomarkers. Potential resources for biomarker validation studies are described. CONCLUSIONS Multisite and multidisciplinary collaboration can facilitate study design strategies in this lethal but low incidence disease and streamline the path from biomarker discovery to clinical use. Improvements in analytical and experimental design methods could help accelerate biomarker evaluation through the phases of biomarker development.
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Affiliation(s)
- Lynette M Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Douglas W Mahoney
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - William R Bamlet
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Fang Yu
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Suyu Liu
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael G Goggins
- Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sourat Darabi
- Hoag Family Cancer Institute, Newport Beach, CA, USA
| | - Shounak Majumder
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Qiao-Li Wang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Gregory A Coté
- Department of Medicine, Oregon Health & Science University, Portland, OR, USA
| | | | - Zhen Zhang
- Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Akhil Chawla
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - Janet E Olson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jeanine M Genkinger
- Department of Epidemiology, Mailman School of Public Health, Columbia University, NY, NY, USA
| | - Kenneth S Zaret
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Randall Brand
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Eugene J Koay
- Department of Gastrointestinal Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ann L Oberg
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
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Song L, Chen Z, Li Y, Ran L, Liao D, Zhang Y, Wang G. Trend and forecast analysis of the changing disease burden of pancreatic cancer attributable to high fasting glucose in China, 1990-2021. Front Oncol 2024; 14:1471699. [PMID: 39493456 PMCID: PMC11527594 DOI: 10.3389/fonc.2024.1471699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 09/25/2024] [Indexed: 11/05/2024] Open
Abstract
Background Pancreatic cancer (PC) is a malignant tumour with poor prognosis and high mortality, and high fasting plasma glucose (HFPG) is considered to be one of its important risk factors. Methods PC disease burden data were obtained from the Global Burden of Disease Study 2021 (GBD 2021) database. Annual percent change (APC), average APC (AAPC), and 95% confidence interval (95% CI) were analysed using joinpoint linkpoint regression models to assess the trend of PC burden of disease between 1990 and 2021. An age-period-cohort model was used to estimate the independent effects of age, period, and cohort on PC burden, and data on PC mortality attributable to HFPG in China from 2022 to 2032 were analysed on the basis of a Bayesian age-period-cohort model projection. Results The number of Pc deaths due to HFPG continue to rise in China from 1990 to 2021, with age-standardised mortality (ASMR) and age-standardised disability-adjusted life-year rates with increasing AAPC values of 1.12% (95% CI, 0.73-1.52) and 1.00% (95% CI, 0.63-1.37), respectively. Throughout the study, we found that the overall level of PC disease burden was significantly higher in men than that in women. In age-period-cohort analyses, the age effect of PC showed an increasing and then decreasing trend, the period effect showed an overall increasing trend during the study period, and the cohort effect showed an overall slow decreasing trend. In addition, the BAPC model predicted that ASMR is expected to decline significantly in both men and women from 2022 to 2032. Conclusions It was found that PC attributable to HFPG was generally on the rise in China from 1990 to 2021 and has been on the decline in recent years, and projections suggest that the country's future PC disease burden will continue to show a downward trend. Age and period of birth are the main factors affecting the disease burden, especially in men and older age groups. Early prevention, regular screening, and research into the pathogenesis of PC have, therefore, become particularly important.
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Affiliation(s)
- Lichen Song
- School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Ziyi Chen
- School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Yongjie Li
- School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Lirong Ran
- School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Dongwei Liao
- School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Yuanyuan Zhang
- Medicine Department, School of Clinical Medicine, Dali University, Dali, Yunnan, China
| | - Guangming Wang
- Center of Genetic Testing, The First Affiliated Hospital of Dali University, Dali, Yunnan, China
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5
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Moreau M, China D, Sy G, Ding K, Ngwa W. Customizable Lyophilized Agent for Radiotherapy Imaging and TherapY (CLARITY). J Funct Biomater 2024; 15:285. [PMID: 39452584 PMCID: PMC11508613 DOI: 10.3390/jfb15100285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Smart radiotherapy biomaterials (SRBs) include seed and liquid biomaterials designed to be employed as fiducial markers during radiotherapy while also delivering therapeutic drug payloads to enhance treatment outcomes. In this study, we investigate a novel Customizable Lyophilized Agent for Radiotherapy Imaging and TherapY (CLARITY) biomaterial, which can be loaded with immunoadjuvants (anti-CD40 monoclonal antibody or Caflanone (FBL-03G)) at the point of care. The CLARITY biomaterial was investigated in an animal model of pancreatic cancer using C57BL6 mice. Mice were imaged before and at different points of time post-treatment to evaluate the potential of CLARITY biomaterial to provide imaging contrast similar to fiducials. This study also used cadavers to assess CLARITY's potential to provide imaging contrast in humans. Results showed imaging contrast from computed tomography (CT) and magnetic resonance imaging (MRI) modalities for up to 30 days post-treatment, demonstrating potential for use as fiducials. A significant increase in survival (***, p = 0.0006) was observed for mice treated with CLARITY biomaterial loaded with immunoadjuvant for up to 10 weeks post-treatment compared to those without treatment. These initial results demonstrate the potential of CLARITY biomaterial to serve as a smart multifunctional radiotherapy biomaterial and provide the impetus for further development and optimization as a point-of-care technology for combination radiotherapy and immunotherapy.
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Affiliation(s)
- Michele Moreau
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.C.); (G.S.); (K.D.)
| | - Debarghya China
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.C.); (G.S.); (K.D.)
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA
| | - Gnagna Sy
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.C.); (G.S.); (K.D.)
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA
| | - Kai Ding
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.C.); (G.S.); (K.D.)
| | - Wilfred Ngwa
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; (D.C.); (G.S.); (K.D.)
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Xu Y, Yang F, Fu D. Prognostic value of para-aortic lymph node metastasis and dissection for pancreatic head ductal adenocarcinoma: a retrospective cohort study. JOURNAL OF PANCREATOLOGY 2024; 7:199-206. [DOI: 10.1097/jp9.0000000000000159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025] Open
Abstract
Background:
Para-aortic lymph node (PALN) metastasis affects approximately 20% of patients with pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PALN metastases and dissection remains unclear.
Methods:
This retrospective cohort study included patients with PDAC of the pancreatic head who had undergone pancreaticoduodenectomy (PD) at our center between January 2017 and December 2020.
Results:
A total of 234 patients were included in the study. PALN dissection improved the median overall survival (OS) without statistical significance (24.1 vs 18.1 months, P = .156). The median recurrence-free survival was significantly longer in the PALN-dissection group than the group without PALN dissection (18.2 vs 11.6 months, P = .040). Conversely, there were no significant differences in the long-term prognosis between the PALN-positive and PALN-negative subgroups in the PALN-dissection group. Multivariate analysis showed that PALN metastasis was not an independent risk factor for OS (hazard ratio: 0.831, 95% confidence interval: 0.538–1.285, P = .406).
Conclusions:
For patients with pancreatic head ductal adenocarcinoma, PD with PALN dissection may achieve survival prolongation and bridge the survival gap between patients with and without PALN metastasis without significantly increasing the perioperative risks.
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Affiliation(s)
- Yecheng Xu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Feng Yang
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
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Bogdanski AM, van Hooft JE, Boekestijn B, Bonsing BA, Wasser MNJM, Klatte DCF, van Leerdam ME. Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer. Fam Cancer 2024; 23:323-339. [PMID: 38619782 PMCID: PMC11255004 DOI: 10.1007/s10689-024-00368-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 02/24/2024] [Indexed: 04/16/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and is associated with a poor prognosis. The majority of these cancers are detected at a late stage, contributing to the bad prognosis. This underscores the need for novel, enhanced early detection strategies to improve the outcomes. While population-based screening is not recommended due to the relatively low incidence of PDAC, surveillance is recommended for individuals at high risk for PDAC due to their increased incidence of the disease. However, the outcomes of pancreatic cancer surveillance in high-risk individuals are not sorted out yet. In this review, we will address the identification of individuals at high risk for PDAC, discuss the objectives and targets of surveillance, outline how surveillance programs are organized, summarize the outcomes of high-risk individuals undergoing pancreatic cancer surveillance, and conclude with a future perspective on pancreatic cancer surveillance and novel developments.
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Affiliation(s)
- Aleksander M Bogdanski
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Bas Boekestijn
- Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Bert A Bonsing
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Martin N J M Wasser
- Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Derk C F Klatte
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Monique E van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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8
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Gancedo SN, Sahores A, Gómez N, Di Siervi N, May M, Yaneff A, de Sousa Serro MG, Fraunhoffer N, Dusetti N, Iovanna J, Shayo C, Davio CA, González B. The xenobiotic transporter ABCC4/MRP4 promotes epithelial mesenchymal transition in pancreatic cancer. Front Pharmacol 2024; 15:1432851. [PMID: 39114357 PMCID: PMC11303182 DOI: 10.3389/fphar.2024.1432851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/01/2024] [Indexed: 08/10/2024] Open
Abstract
The xenobiotic transporter ABCC4/MRP4 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and correlates with a more aggressive phenotype and metastatic propensity. Here, we show that ABCC4 promotes epithelial-mesenchymal transition (EMT) in PDAC, a hallmark process involving the acquisition of mesenchymal traits by epithelial cells, enhanced cell motility, and chemoresistance. Modulation of ABCC4 levels in PANC-1 and BxPC-3 cell lines resulted in the dysregulation of genes present in the EMT signature. Bioinformatic analysis on several cohorts including tumor samples, primary patient-derived cultured cells, patient-derived xenografts, and cell lines, revealed a positive correlation between ABCC4 expression and EMT markers. We also characterized the ABCC4 cistrome and identified four candidate clusters in the distal promoter and intron one that showed differential binding of pro-epithelial FOXA1 and pro-mesenchymal GATA2 transcription factors in low ABCC4-expressing HPAF-II and high ABCC4-expressing PANC-1 xenografts. HPAF-II xenografts showed exclusive binding of FOXA1, and PANC-1 xenografts exclusive binding of GATA2, at ABCC4 clusters, consistent with their low and high EMT phenotype respectively. Our results underscore ABCC4/MRP4 as a valuable prognostic marker and a potential therapeutic target to treat PDAC subtypes with prominent EMT features, such as the basal-like/squamous subtype, characterized by worse prognosis and no effective therapies.
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Affiliation(s)
- S. N. Gancedo
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - A. Sahores
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
| | - N. Gómez
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - N. Di Siervi
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - M. May
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - A. Yaneff
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
| | - M. G. de Sousa Serro
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - N. Fraunhoffer
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, CNRS UMR, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
- Equipe Labellisée La Ligue, Marseille, France
| | - N. Dusetti
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, CNRS UMR, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
- Equipe Labellisée La Ligue, Marseille, France
| | - J. Iovanna
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM, CNRS UMR, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
- Equipe Labellisée La Ligue, Marseille, France
- Hospital de Alta Complejidad El Cruce, Argentina. Universidad Nacional Arturo Jauretche, Buenos Aires, Argentina
| | - C. Shayo
- Instituto de Biología y Medicina Experimental (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
| | - C. A. Davio
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
| | - B. González
- Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
- Programa Franco-argentino de Estudio del Cáncer de Páncreas, Buenos Aires, Argentina
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9
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Saleh O, Shihadeh H, Yousef A, Erekat H, Abdallh F, Al-Leimon A, Elsalhy R, Altiti A, Dajani M, AlBarakat MM. The Effect of Intratumor Heterogeneity in Pancreatic Ductal Adenocarcinoma Progression and Treatment. Pancreas 2024; 53:e450-e465. [PMID: 38728212 DOI: 10.1097/mpa.0000000000002342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
BACKGROUND AND OBJECTIVES Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis. MATERIALS AND METHODS The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered. RESULTS The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations. CONCLUSION Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.
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Affiliation(s)
- Othman Saleh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | - Hana Erekat
- School of medicine, University of Jordan, Amman
| | - Fatima Abdallh
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | | | | | | | - Majd Dajani
- From the Faculty of Medicine, The Hashemite University, Zarqa
| | - Majd M AlBarakat
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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10
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Bhoopathi P, Kumar A, Pradhan AK, Maji S, Mannangatti P, Windle JJ, Subler MA, Zhang D, Vudatha V, Trevino JG, Madan E, Atfi A, Sarkar D, Gogna R, Das SK, Emdad L, Fisher PB. Cytoplasmic-delivery of polyinosine-polycytidylic acid inhibits pancreatic cancer progression increasing survival by activating Stat1-CCL2-mediated immunity. J Immunother Cancer 2023; 11:e007624. [PMID: 37935566 PMCID: PMC10649894 DOI: 10.1136/jitc-2023-007624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective therapies and with poor prognosis, causing 7% of all cancer-related fatalities in the USA. Considering the lack of effective therapies for this aggressive cancer, there is an urgent need to define newer and more effective therapeutic strategies. Polyinosine-polycytidylic acid (pIC) is a synthetic double-stranded RNA (dsRNA) which directly activates dendritic cells and natural killer cells inhibiting tumor growth. When pIC is delivered into the cytoplasm using polyethyleneimine (PEI), pIC-PEI, programmed-cell death is induced in PDAC. Transfection of [pIC]PEI into PDAC cells inhibits growth, promotes toxic autophagy and also induces apoptosis in vitro and in vivo in animal models. METHODS The KPC transgenic mouse model that recapitulates PDAC development in patients was used to interrogate the role of an intact immune system in vivo in PDAC in response to [pIC]PEI. Antitumor efficacy and survival were monitored endpoints. Comprehensive analysis of the tumor microenvironment (TME) and immune cells, cytokines and chemokines in the spleen, and macrophage polarization were analyzed. RESULTS Cytosolic delivery of [pIC]PEI induces apoptosis and provokes strong antitumor immunity in vivo in immune competent mice with PDAC. The mechanism underlying the immune stimulatory properties of [pIC]PEI involves Stat1 activation resulting in CCL2 and MMP13 stimulation thereby provoking macrophage polarization. [pIC]PEI induces apoptosis via the AKT-XIAP pathway, as well as macrophage differentiation and T-cell activation via the IFNγ-Stat1-CCL2 signaling pathways in PDAC. In transgenic tumor mouse models, [pIC]PEI promotes robust and profound antitumor activity implying that stimulating the immune system contributes to biological activity. The [pIC]PEI anti-PDAC effects are enhanced when used in combination with a standard of care (SOC) treatment, that is, gemcitabine. CONCLUSIONS In summary, [pIC]PEI treatment is non-toxic toward normal pancreatic cells while displaying strong cytotoxic and potent immune activating activities in PDAC, making it an attractive therapeutic when used alone or in conjunction with SOC therapeutic agents, potentially providing a safe and effective treatment protocol with translational potential for the effective therapy of PDAC.
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Affiliation(s)
- Praveen Bhoopathi
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Amit Kumar
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Anjan K Pradhan
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Santanu Maji
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Padmanabhan Mannangatti
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Jolene J Windle
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Mark A Subler
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Dongyu Zhang
- Surgery, Division of Surgical Oncology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Vignesh Vudatha
- Surgery, Division of Surgical Oncology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Jose G Trevino
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- Surgery, Division of Surgical Oncology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Esha Madan
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- Surgery, Division of Surgical Oncology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Azeddine Atfi
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Devanand Sarkar
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Rajan Gogna
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Swadesh K Das
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Luni Emdad
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
| | - Paul B Fisher
- Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
- VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA
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11
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Zhu S, Yang H, Liu L, Jiang Z, Ji J, Wang X, Zhong L, Liu F, Gao X, Wang H, Zhou Y. CDKs Functional Analysis in Low Proliferating Early-Stage Pancreatic Ductal Adenocarcinoma. JOURNAL OF BIOINFORMATICS AND SYSTEMS BIOLOGY : OPEN ACCESS 2023; 6:187-200. [PMID: 37744402 PMCID: PMC10516534 DOI: 10.26502/jbsb.5107060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a poor prognosis and growing incidence. In this study, we explored the potential roles of CDK1, CDK2, CDK4, and CDK6 in the progression of early-stage PDAC. Clinicopathologic and mRNA expression data and treatment information of 140 patients identified with stage I/II PDAC who underwent pancreaticoduodenectomy were obtained from the Cancer Genome Atlas data set. Our bioinformatic analysis showed that higher CDK1, CDK2, CDK4, or CDK6 expression was associated with a shorter median survival of the early-stage PDAC patients. Of note, in the low-proliferating pancreatic cancer group, CDKs expressions were significantly associated with proteins functioning in apoptosis, metastasis, immunity, or stemness. Among the low-proliferating PDAC, higher expression of CDK1 was associated with the shorter survival of patients, suggesting that CDK1 may regulate PDAC progression through cell cycle-independent mechanisms. Our experimental data showed that CDK1 knockdown/inhibition significantly suppressed the expression levels of AHR and POU5F1, two critical proteins functioning in cancer cell metastasis and stemness, in low-proliferating, but not in high-proliferating pancreatic cancer cells. In all, our study suggests that CDKs regulate PDAC progression not only through cell proliferation but also through apoptosis, metastasis, immunity, and stemness.
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Affiliation(s)
- Shikai Zhu
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
- Organ Transplant Center, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
| | - Huining Yang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
| | - Lingling Liu
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics
| | - Zhilin Jiang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
| | - Juanjuan Ji
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
| | - Xiao Wang
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
| | - Lin Zhong
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
| | - Fulin Liu
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
| | - Xueliang Gao
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Haizhen Wang
- Department of Cell and Molecular Pharmacology & Experimental Therapeutics
- Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yu Zhou
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, School of Medicine,University of Electronic Science and Technology of China, Chengdu, China
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12
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Palma AM, Bushnell GG, Wicha MS, Gogna R. Tumor microenvironment interactions with cancer stem cells in pancreatic ductal adenocarcinoma. Adv Cancer Res 2023; 159:343-372. [PMID: 37268400 PMCID: PMC11218813 DOI: 10.1016/bs.acr.2023.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer in the United States. Additionally, the low survival rate makes PDAC the third-leading cause of cancer-related mortality in the United States, and it is projected that by 2030, it will become the second-leading cause of cancer mortality. Several biological factors contribute to PDAC aggressiveness, and their understanding will narrow the gap from biology to clinical care of PDAC, leading to earlier diagnoses and the development of better treatment options. In this review, we describe the origins of PDAC highlighting the role of cancer stem cells (CSC). CSC, also known as tumor initiating cells, which exhibit a unique metabolism that allows them to maintain a highly plastic, quiescent, immune- and therapy-evasive state. However, CSCs can exit quiescence during proliferation and differentiation, with the capacity to form tumors while constituting a small population in tumor tissues. Tumorigenesis depends on the interactions between CSCs and other cellular and non-cellular components in the microenvironment. These interactions are fundamental to support CSC stemness and are maintained throughout tumor development and metastasis. PDAC is characterized by a massive desmoplastic reaction, which result from the deposition of high amounts of extracellular matrix components by stromal cells. Here we review how this generates a favorable environment for tumor growth by protecting tumor cells from immune responses and chemotherapy and inducing tumor cell proliferation and migration, leading to metastasis formation ultimately leading to death. We emphasize the interactions between CSCs and the tumor microenvironment leading to metastasis formation and posit that better understanding and targeting of these interactions will improve patient outcomes.
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Affiliation(s)
| | - Grace G Bushnell
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Max S Wicha
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
| | - Rajan Gogna
- VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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13
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Sereti E, Papapostolou I, Dimas K. Pancreatic Cancer Organoids: An Emerging Platform for Precision Medicine? Biomedicines 2023; 11:890. [PMID: 36979869 PMCID: PMC10046065 DOI: 10.3390/biomedicines11030890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/14/2023] [Accepted: 02/19/2023] [Indexed: 03/17/2023] Open
Abstract
Despite recent therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, with remarkable resistance to treatment, poor prognosis, and poor clinical outcome. More efficient therapeutic approaches are urgently needed to improve patients' survival. Recently, the development of organoid culture systems has gained substantial attention as an emerging preclinical research model. PDAC organoids have been developed to study pancreatic cancer biology, progression, and treatment response, filling the translational gap between in vitro and in vivo models. Here, we review the rapidly evolving field of PDAC organoids and their potential as powerful preclinical tools that could pave the way towards precision medicine for pancreatic cancer.
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Affiliation(s)
- Evangelia Sereti
- Department of Translational Medicine, Lund University, 22363 Lund, Sweden
| | - Irida Papapostolou
- Department of Biochemistry and Molecular Medicine, 3012 Bern, Switzerland
| | - Konstantinos Dimas
- Department of Pharmacology, University of Thessaly, Biopolis, 41500 Larissa, Greece
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14
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Ong DY, How GY, Pua U. Irreversible electroporation of the pancreas - A decade on. J Interv Med 2023; 6:10-13. [PMID: 37180371 PMCID: PMC10167507 DOI: 10.1016/j.jimed.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/13/2022] [Accepted: 10/11/2022] [Indexed: 05/16/2023] Open
Abstract
Irreversible electroporation (IRE) employs the use of an electric field to cause irreversible permeability of the cell membrane, inducing apoptosis. The use of IRE for locally advanced pancreatic cancer (LAPC) was first described in 2012. The crucial advantage of IRE compared with other devices employing thermal ablation is the safety around vital structures such as vessels and ducts. This makes it an attractive option for use in the pancreas due to the close proximity of multiple major vascular structures, biliary ducts, and adjacent gastrointestinal organs. Over the past decade, IRE has established itself as a useful treatment adjunct and may soon become the standard of care, particularly for LAPC. This article will explore the current evidence and provide a concise summary of pertinent issues, including patient selection, preoperative management, clinical outcomes, radiological response and future prospects of IRE in pancreatic cancer.
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Affiliation(s)
- Daniel Yuxuan Ong
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, Singapore
| | - Guo Yuan How
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, Singapore
| | - Uei Pua
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, Singapore
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15
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Liang F, Lv Y, Qiao X, Zhang S, Shen S, Wang C, Xu G, Zou X, Wang L, Zhang B. Cinchonine-induced cell death in pancreatic cancer cells by downregulating RRP15. Cell Biol Int 2023; 47:907-919. [PMID: 36682038 DOI: 10.1002/cbin.11987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 11/09/2022] [Accepted: 01/02/2023] [Indexed: 01/23/2023]
Abstract
Pancreatic cancer is characterized by poor prognosis and high mortality, while its treatment remains unsatisfactory. Cinchonine, a natural compound present in cinchona bark, is a potential anticancer drug. Whether cinchonine is of relevance to pancreatic cancer therapeutics is unclear. This research showed that the ribosomal RNA-processing 15 homolog (RRP15) expression is decreased in the pancreatic cancer, and RRP15 knockdown inhibited autophagy, and caused apoptosis in pancreatic cancer cells. Cinchonine treatment inhibits the expression of RRP15 and autophagy, and caused apoptosis by leading to the activation of Nrf2 axis in pancreatic cancer cells. Taken together, the above results indicate that cinchonine treatment inhibited autophagy and induced apoptosis through activating Nrf2 axis by downregulating RRP15 in pancreatic cancer cells.
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Affiliation(s)
- Feng Liang
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Gastroenterology, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Ying Lv
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiao Qiao
- Department of Gastroenterology, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Shu Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Shanshan Shen
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Changcheng Wang
- Department of Gastroenterology, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, China
| | - Guifang Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Gastroenterology, Affilated Taikang Xianlin Drum Tower Hospital, Medical school of Nanjing University, Nanjing, Jiangsu, China
| | - Lei Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Bin Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.,Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
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16
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Abstract
BACKGROUND Detecting pancreatic cancer at an earlier stage may contribute to an increased survival. Patients with stage I pancreatic cancer have a 5-year survival rate of 36%, while stage IV patients have a 5-year survival rate of 1% in Sweden. Research into novel blood-based biomarkers for pancreatic cancer is highly intensive and innovative, but has yet to result in any routine screening test. The aim of this study was to evaluate the specificity and sensitivity of a hypothetical blood test for pancreatic cancer used for screening purposes and the economic aspects of testing. METHOD A model of a screening test was created, with varying specificity and sensitivity both set at 80%, 85%, 90%, 95% or 99% and applied to selected risk groups. Excessive costs of false positive screening outcomes, QALYs, ICERs and total costs were calculated. RESULTS Individuals with family history and genetic mutations associated with pancreatic cancer, new-onset diabetes ≥50 years of age and early symptoms had the highest positive predictive values and ICERs beneath the willingness-to-pay-level of EUR 100,000/QALY. Screening of the general population and smokers resulted in a high rate of false positive cases and extensive extra costs. CONCLUSIONS General screening for pancreatic cancer is not cost-effective, while screening of certain high-risk groups may be economically justified given the availability of a high-performing blood-based test.
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Affiliation(s)
- Tomasz Draus
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
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17
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Liposomal co-delivery system encapsulating celastrol and paclitaxel displays highly enhanced efficiency and low toxicity against pancreatic cancer. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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18
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Liu L, An X, Schaefer M, Yan B, de la Torre C, Hillmer S, Gladkich J, Herr I. Nanosilver inhibits the progression of pancreatic cancer by inducing a paraptosis-like mixed type of cell death. Biomed Pharmacother 2022; 153:113511. [PMID: 36076598 DOI: 10.1016/j.biopha.2022.113511] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/28/2022] [Accepted: 07/30/2022] [Indexed: 11/25/2022] Open
Abstract
Silver has been in clinical use since ancient times and silver nanoparticles (AgNPs) have attracted attention in cancer therapy. We investigated the mechanisms by which AgNPs inhibit pancreatic ductal adenocarcinoma (PDAC). AgNPs were synthesized and 3 human PDAC and 2 nonmalignant primary cell lines were treated with AgNPs. MTT, MAPK, colony, spheroid and scratch assays, Western blotting, TEM, annexin V, 7-AAD, and H2DCFDA staining, FACS analysis, mRNA array and bioinformatics analyses, tumor xenograft transplantation, and immunohistochemistry of the treated cells were performed. We found that minimal AgNPs amounts selectively eradicated PDAC cells within a few hours. AgNPs inhibited cell migration and spheroid and colony formation, damaged mitochondria, and induced paraptosis-like cell death with the presence of cytoplasmic vacuoles, dilation of the ER and mitochondria, ROS formation, MAPK activity, and p62 and LC3b expression, whereas effects on the nucleus, DNA fragmentation, or caspases were not detectable. AgNPs strongly decreased tumor xenograft growth without side effects and reduced the expression of markers for proliferation and DNA repair, but upregulated paraptosis markers. The results highlight nanosilver as complementary agent to improve the therapeutic efficacy in pancreatic cancer.
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Affiliation(s)
- Li Liu
- Section Surgical Research, Molecular OncoSurgery, Department of General, Visceral and Transplantation Surgery, Ruprecht Karls University of Heidelberg, Medical Faculty Heidelberg, Germany.
| | - XueFeng An
- Section Surgical Research, Molecular OncoSurgery, Department of General, Visceral and Transplantation Surgery, Ruprecht Karls University of Heidelberg, Medical Faculty Heidelberg, Germany.
| | - Michael Schaefer
- Section Surgical Research, Molecular OncoSurgery, Department of General, Visceral and Transplantation Surgery, Ruprecht Karls University of Heidelberg, Medical Faculty Heidelberg, Germany.
| | - Bin Yan
- Section Surgical Research, Molecular OncoSurgery, Department of General, Visceral and Transplantation Surgery, Ruprecht Karls University of Heidelberg, Medical Faculty Heidelberg, Germany.
| | - Carolina de la Torre
- Microarray Analytics - NPGS Core Facility, Medical Faculty Mannheim, Ruprecht Karls University of Heidelberg, Heidelberg, Germany.
| | - Stefan Hillmer
- Electron Microscopy Core Facility, University of Heidelberg, Heidelberg, Germany.
| | - Jury Gladkich
- Section Surgical Research, Molecular OncoSurgery, Department of General, Visceral and Transplantation Surgery, Ruprecht Karls University of Heidelberg, Medical Faculty Heidelberg, Germany.
| | - Ingrid Herr
- Section Surgical Research, Molecular OncoSurgery, Department of General, Visceral and Transplantation Surgery, Ruprecht Karls University of Heidelberg, Medical Faculty Heidelberg, Germany.
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19
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Vitto VAM, Bianchin S, Zolondick AA, Pellielo G, Rimessi A, Chianese D, Yang H, Carbone M, Pinton P, Giorgi C, Patergnani S. Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy. Biomedicines 2022; 10:1596. [PMID: 35884904 PMCID: PMC9313210 DOI: 10.3390/biomedicines10071596] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/25/2022] [Accepted: 06/30/2022] [Indexed: 01/18/2023] Open
Abstract
Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.
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Affiliation(s)
- Veronica Angela Maria Vitto
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Silvia Bianchin
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alicia Ann Zolondick
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
- Department of Molecular Biosciences and Bioengineering, University of Hawai’i at Manoa, Honolulu, HI 96816, USA
| | - Giulia Pellielo
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Alessandro Rimessi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Diego Chianese
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Haining Yang
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96816, USA; (A.A.Z.); (H.Y.); (M.C.)
| | - Paolo Pinton
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Carlotta Giorgi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
| | - Simone Patergnani
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Science, University of Ferrara, 44121 Ferrara, Italy; (V.A.M.V.); (S.B.); (G.P.); (A.R.); (D.C.); (P.P.)
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20
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Lin KW, Ang TL, Li JW. Role of artificial intelligence in early detection and screening for pancreatic adenocarcinoma. Artif Intell Med Imaging 2022; 3:21-32. [DOI: 10.35711/aimi.v3.i2.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/12/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma remains to be one of the deadliest malignancies in the world despite treatment advancement over the past few decades. Its low survival rates and poor prognosis can be attributed to ambiguity in recommendations for screening and late symptom onset, contributing to its late presentation. In the recent years, artificial intelligence (AI) as emerged as a field to aid in the process of clinical decision making. Considerable efforts have been made in the realm of AI to screen for and predict future development of pancreatic ductal adenocarcinoma. This review discusses the use of AI in early detection and screening for pancreatic adenocarcinoma, and factors which may limit its use in a clinical setting.
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Affiliation(s)
- Kenneth Weicong Lin
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - Tiing Leong Ang
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - James Weiquan Li
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
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21
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Vance K, Alitinok A, Winfree S, Jensen-Smith H, Swanson BJ, Grandgenet PM, Klute KA, Crichton DJ, Hollingsworth MA. Machine learning analyses of highly-multiplexed immunofluorescence identifies distinct tumor and stromal cell populations in primary pancreatic tumors. Cancer Biomark 2022; 33:219-235. [PMID: 35213363 PMCID: PMC9278645 DOI: 10.3233/cbm-210308] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge for patients and clinicians. OBJECTIVE To analyze the distribution of 31 different markers in tumor and stromal portions of the tumor microenvironment (TME) and identify immune cell populations to better understand how neoplastic, non-malignant structural, and immune cells, diversify the TME and influence PDAC progression. METHODS Whole slide imaging (WSI) and cyclic multiplexed-immunofluorescence (MxIF) was used to collect 31 different markers over the course of nine distinctive imaging series of human PDAC samples. Image registration and machine learning algorithms were developed to largely automate an imaging analysis pipeline identifying distinct cell types in the TME. RESULTS A random forest algorithm accurately predicted tumor and stromal-rich areas with 87% accuracy using 31 markers and 77% accuracy using only five markers. Top tumor-predictive markers guided downstream analyses to identify immune populations effectively invading into the tumor, including dendritic cells, CD4+ T cells, and multiple immunoregulatory subtypes. CONCLUSIONS Immunoprofiling of PDAC to identify differential distribution of immune cells in the TME is critical for understanding disease progression, response and/or resistance to treatment, and the development of new treatment strategies.
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Affiliation(s)
- Krysten Vance
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Alphan Alitinok
- Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA
| | - Seth Winfree
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Heather Jensen-Smith
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Benjamin J. Swanson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paul M. Grandgenet
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kelsey A. Klute
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Daniel J. Crichton
- Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA
| | - Michael A. Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
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22
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Neoadjuvant Treatment Lowers the Risk of Mesopancreatic Fat Infiltration and Local Recurrence in Patients with Pancreatic Cancer. Cancers (Basel) 2021; 14:cancers14010068. [PMID: 35008232 PMCID: PMC8750596 DOI: 10.3390/cancers14010068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/10/2021] [Accepted: 12/21/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary After the implementation of an in-depth histopathological pancreas protocol, curative resection rates for pancreatic head cancers have drastically dropped. Standardized extended resections using embryo-anatomic landmarks (MPE), have recently been prooved to increase margin-negative resection rates. The mesopancreatic fat, excised during these extended resections, was infiltrated in the majority of the patients. Neoadjuvant treatment is an emerging topic of interest for pancreatic cancer patients. It remains unclear if these extended resections are still warranted in patients after neoadjuvant treatment. Neoadjuvant treatment lowered the risk for mesopancreatic fat infiltration and patients were less prone to local recurrence and margin positive resections when compared to patients after upfront surgery. However, the majority of the patients are yet diagnosed with mesopancreatic fat infiltration, justifying this extended approach synergistically with the treatment strategies for colorectal cancer. Abstract Background: Survival following surgical treatment of ductal adenocarcinoma of the pancreas (PDAC) remains poor. The recent implementation of the circumferential resection margin (CRM) into standard histopathological evaluation lead to a significant reduction in R0 rates. Mesopancreatic fat infiltration is present in ~80% of PDAC patients at the time of primary surgery and recently, mesopancreatic excision (MPE) was correlated to complete resection. To attain an even higher rate of R0(CRM−) resections in the future, neoadjuvant therapy in patients with a progressive disease seems a promising tool. We analyzed radiographic and histopathological treatment response and mesopancreatic tumor infiltration in patients who received neoadjuvant therapy prior to MPE. The aim of our study was to evaluate the need for MPE following neoadjuvant therapy and if multi-detector computed tomographically (MDCT) evaluated treatment response correlates with mesopancreatic (MP) infiltration. Method: Radiographic, clinicopathological and survival parameters of 27 consecutive patients who underwent neoadjuvant therapy prior to MPE were evaluated. The mesopancreatic fat tissue was histopathologically analyzed and the 1 mm-rule (CRM) was applied. Results: In the study collective, both the rate of R0 resection R0(CRM−) and the rate of mesopancreatic fat infiltration was 62.9%. Patients with MP infiltration showed a lower tumor response. Surgical resection status was dependent on MP infiltration and tumor response status. Patients with MDCT-predicted tumor response were less prone to MP infiltration. When compared to patients after upfront surgery, MP infiltration and local recurrence rate was significantly lower after neoadjuvant treatment. Conclusion: MPE remains warranted after neoadjuvant therapy. Mesopancreatic fat invasion was still evident in the majority of our patients following neoadjuvant treatment. MDCT-predicted tumor response did not exclude mesopancreatic fat infiltration.
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Zhu B, Wu X, Guo T, Guan N, Liu Y. Epidemiological Characteristics of Pancreatic Cancer in China From 1990 to 2019. Cancer Control 2021; 28:10732748211051536. [PMID: 34713730 PMCID: PMC8558605 DOI: 10.1177/10732748211051536] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background Pancreatic cancer is an aggressive cancer and is predicted to become the second leading cause of cancer-related deaths in China. To understand the epidemic trend of pancreatic cancer and formulate targeted preventive measures, it is important to analyze the incidence and mortality of pancreatic cancer. Methods The incidence and mortality data of pancreatic cancer in China were obtained from Global Burden of Disease (GBD) data. We used joinpoint regression analysis to calculate the magnitude and direction of trends, and the age-period-cohort method to analyze the effects of chronological age, time period, and birth cohort. Results The age-standardized rates (ASRs) for both incidence and mortality of pancreatic cancer increased from 1990 to 2019, and were higher in males than females. The incidence and mortality rates have increased year by year in the age group above 25 years. The most common age group was 55–79 years, accounting for approximately 50% of all incident cases. In terms of incidence and mortality rates, the overall net drifts were above 0. The local drifts in all age groups were above 0 in both sexes and males, while the local drifts in the 15–39 age groups were below 0 in females. The longitudinal age curves increased with age, with higher incidence and mortality rates, mainly in older age groups. The period rate ratios increased by year. The cohort rate ratios showed an upward trend before 1970 and fluctuated after 1975. Conclusions The burden of pancreatic cancer is still very high in China, and attention should be paid to the key population that is, males and older people. The results of our study can be used by policy makers to allocate resources efficiently to improve early diagnosis and treatment, improving the awareness of self-protection, and advocating a healthy lifestyle to prevent pancreatic cancer.
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Affiliation(s)
- Bo Zhu
- Department of Cancer Prevention and Treatment, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Xiaomei Wu
- Department of Clinical Epidemiology and Center of Evidence Based Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Tianyu Guo
- Department of Hepatobiliary surgery, 74665Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Ning Guan
- Center of medical examination, 74665Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Yefu Liu
- Department of Hepatobiliary surgery, 74665Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
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24
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Pre-Operative MDCT Staging Predicts Mesopancreatic Fat Infiltration-A Novel Marker for Neoadjuvant Treatment? Cancers (Basel) 2021; 13:cancers13174361. [PMID: 34503170 PMCID: PMC8430607 DOI: 10.3390/cancers13174361] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 08/23/2021] [Indexed: 01/05/2023] Open
Abstract
The rates of microscopic incomplete resections (R1/R0CRM+) in patients receiving standard pancreaticoduodenectomy for PDAC remain very high. One reason may be the reported high rates of mesopancreatic fat infiltration. In this large cohort study, we used available histopathological specimens of the retropancreatic fat and correlated high resolution CT-scans with the microscopic tumor infiltration of this area. We found that preoperative MDCT scans are suitable to detect cancerous infiltration of this mesopancreatic tissue and this, in turn, was a significant indicator for both incomplete surgical resection (R1/R0CRM+) and worse overall survival. These findings indicate that a neoadjuvant treatment in PDAC patients with CT-morphologically positive infiltration of the mesopancreas may result in better local control and thus improved resection rates. Mesopancreatic fat stranding should thus be considered in the decision for neoadjuvant therapy. Background: Due to the persistently high rates of R1 resections, neoadjuvant treatment and mesopancreatic excision (MPE) for ductal adenocarcinoma of the pancreatic head (hPDAC) have recently become a topic of interest. While radiographic cut-off for borderline resectability has been described, the necessary extent of surgery has not been established. It has not yet been elucidated whether pre-operative multi-detector computed tomography (MDCT) staging reliably predicts local mesopancreatic (MP) fat infiltration and tumor extension. Methods: Two hundred and forty two hPDAC patients that underwent MPE were analyzed. Radiographic re-evaluation was performed on (1) mesopancreatic fat stranding (MPS) and stranding to peripancreatic vessels, as well as (2) tumor diameter and anatomy, including contact to peripancreatic vessels (SMA, GDA, CHA, PV, SMV). Routinely resected mesopancreatic and perivascular (SMA and PV/SMV) tissue was histopathologically re-analyzed and histopathology correlated with radiographic findings. A logistic regression of survival was performed. Results: MDCT-predicted tumor diameter correlated with pathological T-stage, whereas presumed tumor contact and fat stranding to SMA and PV/SMV predicted and correlated with histological cancerous infiltration. Importantly, mesopancreatic fat stranding predicted MP cancerous infiltration. Positive MP infiltration was evident in over 78%. MPS and higher CT-predicted tumor diameter correlated with higher R1 resection rates. Patients with positive MP stranding had a significantly worse overall survival (p = 0.023). Conclusions: A detailed preoperative radiographic assessment can predict mesopancreatic infiltration and tumor morphology and should influence the decision for primary surgery, as well as the extent of surgery. To increase the rate of R0CRM- resections, MPS should be considered in the decision for neoadjuvant therapy.
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25
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Safi SA, Rehders A, Haeberle L, Fung S, Lehwald N, Esposito I, Ziayee F, Krieg A, Knoefel WT, Fluegen G. Para-aortic lymph nodes and ductal adenocarcinoma of the pancreas: Distant neighbors? Surgery 2021; 170:1807-1814. [PMID: 34392977 DOI: 10.1016/j.surg.2021.06.045] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/07/2021] [Accepted: 06/24/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Para-aortic lymph nodes in the ductal adenocarcinoma of the pancreatic head are regarded as distant metastases. Chemotherapy is considered the only treatment option if para-aortic lymph nodes metastases are detected preoperatively or intraoperatively. The role of standardized para-aortic lymph node lymphadenectomy during pancreaticoduodenectomy remains controversial. The aim of this study was to evaluate complication profiles and survival. METHODS All cases of ductal adenocarcinoma of the pancreatic head were evaluated from a prospectively maintained database (n = 289). Para-aortic lymph node lymphadenectomy was routinely performed in all patients with suspected ductal adenocarcinoma of the pancreatic head. Subgroup analysis was performed between patients with histologically positive (+) and negative (-) para-aortic lymph nodes. Patients receiving pancreaticoduodenectomy without para-aortic lymph node lymphadenectomy for other causes served as a control group. RESULTS A total of 192 patients received para-aortic lymph node lymphadenectomy, of which 41 were positive for para-aortic lymph node metastases. In 97 patients with ductal adenocarcinoma of the pancreatic head, no para-aortic lymph node lymphadenectomy was performed owing to postoperative pancreatic ductal adenocarcinoma diagnosis. Clinicopathologic data were homogenously distributed. Hospital stay and postoperative morbidity demonstrated no significant difference between the 3 subgroups. The median overall survival of 19.63 months (95% confidence interval: 14.57-24.79 months) in para-aortic lymph node- patients was not statistically different when compared with the median overall survival of 18.22 months (95% confidence interval: 12.68-23.75 months) in para-aortic lymph node + patients (log-rank test P = .223). Preoperative computed tomography was a poor predictor for para-aortic lymph node status (sensitivity = 10.3%, specificity = 97.8%). CONCLUSION This study represents the largest cohort receiving routine para-aortic lymph node lymphadenectomy. Extended lymphadenectomy can be performed safely and, although disease-free survival of para-aortic lymph node+ patients was significantly shorter, overall survival and postrelapse survival were on par with that of para-aortic lymph node- patients. Preoperative computed tomography indicating para-aortic lymph node metastasis should not preclude curative resection.
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Affiliation(s)
- Sami A Safi
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Alexander Rehders
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Lena Haeberle
- Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Stephen Fung
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Nadja Lehwald
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Irene Esposito
- Institute of Pathology, Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Farid Ziayee
- Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Andreas Krieg
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
| | - Wolfram T Knoefel
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany.
| | - Georg Fluegen
- Department of Surgery (A), Medical Faculty, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany
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26
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Gallo M, Adinolfi V, Morviducci L, Acquati S, Tuveri E, Ferrari P, Zatelli MC, Faggiano A, Argentiero A, Natalicchio A, D'Oronzo S, Danesi R, Gori S, Russo A, Montagnani M, Beretta GD, Di Bartolo P, Silvestris N, Giorgino F. Early prediction of pancreatic cancer from new-onset diabetes: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper. ESMO Open 2021; 6:100155. [PMID: 34020401 PMCID: PMC8144346 DOI: 10.1016/j.esmoop.2021.100155] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer (PC) is a common cause of cancer-related death, due to difficulties in detecting early-stage disease, to its aggressive behaviour, and to poor response to systemic therapy. Therefore, developing strategies for early diagnosis of resectable PC is critical for improving survival. Diabetes mellitus is another major public health problem worldwide. Furthermore, diabetes can represent both a risk factor and a consequence of PC: nowadays, the relationship between these two diseases is considered a high priority for research. New-onset diabetes can be an early manifestation of PC, especially in a thin adult without a family history of diabetes. However, even if targeted screening for patients at higher risk of PC could be a promising approach, this is not recommended in asymptomatic adults with new-onset diabetes, due to the much higher incidence of hyperglycaemia than PC and to the lack of a safe and affordable PC screening test. Prompted by a well-established and productive multidisciplinary cooperation, the Italian Association of Medical Oncology (AIOM), the Italian Medical Diabetologists Association (AMD), the Italian Society of Endocrinology (SIE), and the Italian Society of Pharmacology (SIF) here review available evidence on the mechanisms linking diabetes and PC, addressing the feasibility of screening for early PC in patients with diabetes, and sharing a set of update statements with the aim of providing a state-of-the-art overview and a decision aid tool for daily clinical practice.
The incidence of PC is increasing and its prognosis is very poor; therefore, early detection is fundamental. New-onset diabetes may be an early manifestation of PC, often disappearing after its resection. Screening for PC is not currently recommended among people with new-onset diabetes, due to its high incidence. Thin subjects >50 years old at the time of diabetes onset, with sudden weight loss and severe hyperglycaemia are at higher risk. Currently some clinical models are promising for stratifying cancer risk in people with new-onset diabetes.
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Affiliation(s)
- M Gallo
- Endocrinology and Metabolic Diseases Unit of AO SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria, Italy.
| | - V Adinolfi
- Endocrinology and Diabetology Unit, ASL Verbano Cusio Ossola, Domodossola, Italy
| | - L Morviducci
- Diabetology and Nutrition Unit, Department of Medical Specialities, ASL Roma 1 - S. Spirito Hospital, Rome, Italy
| | - S Acquati
- Endocrinology Unit, Ospedale Pierantoni-Morgagni, Forlì, Italy
| | - E Tuveri
- Diabetology, Endocrinology and Metabolic Diseases Service, ATS Sardegna - ASSL Carbonia-Iglesias, Italy
| | - P Ferrari
- Palliative Care Unit, Istituti Clinici Scientifici Maugeri SPA SB, IRCCS, Pavia, Italy
| | - M C Zatelli
- Section of Endocrinology & Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical & Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - A Argentiero
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - A Natalicchio
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - S D'Oronzo
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - R Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - S Gori
- Oncologia Medica, IRCCS Ospedale Don Calabria-Sacro Cuore di Negrar, Verona, Italy
| | - A Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - M Montagnani
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - G D Beretta
- Medical Oncology Department, Humanitas Gavazzeni, Bergamo, Italy
| | - P Di Bartolo
- Ravenna Diabetes Center, Romagna Diabetes Managed Clinical Network - Romagna Local Health Authority, Ravenna, Italy
| | - N Silvestris
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy; Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - F Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
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Kenner B, Chari ST, Kelsen D, Klimstra DS, Pandol SJ, Rosenthal M, Rustgi AK, Taylor JA, Yala A, Abul-Husn N, Andersen DK, Bernstein D, Brunak S, Canto MI, Eldar YC, Fishman EK, Fleshman J, Go VLW, Holt JM, Field B, Goldberg A, Hoos W, Iacobuzio-Donahue C, Li D, Lidgard G, Maitra A, Matrisian LM, Poblete S, Rothschild L, Sander C, Schwartz LH, Shalit U, Srivastava S, Wolpin B. Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review. Pancreas 2021; 50:251-279. [PMID: 33835956 PMCID: PMC8041569 DOI: 10.1097/mpa.0000000000001762] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ABSTRACT Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.
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Affiliation(s)
| | - Suresh T. Chari
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - David S. Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Stephen J. Pandol
- Basic and Translational Pancreas Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY
| | | | - Adam Yala
- Department of Electrical Engineering and Computer Science
- Jameel Clinic, Massachusetts Institute of Technology, Cambridge, MA
| | - Noura Abul-Husn
- Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine, Mount Sinai, New York, NY
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | | | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Marcia Irene Canto
- Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yonina C. Eldar
- Department of Math and Computer Science, Weizmann Institute of Science, Rehovot, Israel
| | - Elliot K. Fishman
- Department of Radiology and Radiological Science, Johns Hopkins Medicine, Baltimore, MD
| | | | - Vay Liang W. Go
- UCLA Center for Excellence in Pancreatic Diseases, University of California, Los Angeles, Los Angeles, CA
| | | | - Bruce Field
- From the Kenner Family Research Fund, New York, NY
| | - Ann Goldberg
- From the Kenner Family Research Fund, New York, NY
| | | | - Christine Iacobuzio-Donahue
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Debiao Li
- Biomedical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Anirban Maitra
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | | | | | - Lawrence H. Schwartz
- Department of Radiology, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, NY
| | - Uri Shalit
- Faculty of Industrial Engineering and Management, Technion—Israel Institute of Technology, Haifa, Israel
| | - Sudhir Srivastava
- Division of Cancer Prevention, National Cancer Institute, Bethesda, MD
| | - Brian Wolpin
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA
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Piffoux M, Eriau E, Cassier PA. Autophagy as a therapeutic target in pancreatic cancer. Br J Cancer 2021; 124:333-344. [PMID: 32929194 PMCID: PMC7852577 DOI: 10.1038/s41416-020-01039-5] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 06/22/2020] [Accepted: 08/03/2020] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.
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Affiliation(s)
- Max Piffoux
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
- INSERM UMR 1197-Interaction cellules souches-niches: physiologie, tumeurs et réparation tissulaire, Villejuif, France
- Laboratoire matière et systèmes complexes, Université de Paris, Paris, France
| | - Erwan Eriau
- Team 11 « Metabolism, Cancer, Immunity », UMR S1138, Centre de Recherche des Cordeliers, Paris, France
| | - Philippe A Cassier
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
- TGFβ and Pancreatic Cancer Lab, UMR INSERM 1052 - CNRS 5286, Centre de Recherche en Cancérologie de LYON (CRCL), Centre Léon Bérard, Lyon, France.
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29
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Marcon F, Zuo J, Pearce H, Nicol S, Margielewska-Davies S, Farhat M, Mahon B, Middleton G, Brown R, Roberts KJ, Moss P. NK cells in pancreatic cancer demonstrate impaired cytotoxicity and a regulatory IL-10 phenotype. Oncoimmunology 2020; 9:1845424. [PMID: 33299656 PMCID: PMC7714501 DOI: 10.1080/2162402x.2020.1845424] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common tumor subtypes and remains associated with very poor survival. T cell infiltration into tumor tissue is associated with improved clinical outcome but little is known regarding the potential role of NK cells in disease control. Here we analyze the phenotype and function of NK cells in the blood and tumor tissue from patients with PDAC. Peripheral NK cells are present in normal numbers but display a CD16hiCD57hi phenotype with marked downregulation of NKG2D. Importantly, these cells demonstrate reduced cytotoxic activity and low levels of IFN-γ expression but instead produce high levels of intracellular IL-10, an immunoregulatory cytokine found at increased levels in the blood of PDAC patients. In contrast, NK cells are largely excluded from tumor tissue where they display strong downregulation of both CD16 and CD57, a phenotype that was recapitulated in primary NK cells following co-culture with PDAC organoids. Moreover, expression of activatory proteins, including DNAM-1 and NKP30, was markedly suppressed and the DNAM-1 ligand PVR was strongly expressed on tumor cells. As such, in situ and peripheral NK cells display differential features in patients with PDAC and indicate local and systemic mechanisms by which the tumor can evade immune control. These findings offer a number of potential options for NK-based immunotherapy in the management of patients with PDAC.
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Affiliation(s)
- Francesca Marcon
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham;UK
| | - Jianmin Zuo
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Hayden Pearce
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Samantha Nicol
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Sandra Margielewska-Davies
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Mustafa Farhat
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Brinder Mahon
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham;UK
| | - Gary Middleton
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Rachel Brown
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham;UK
| | - Keith J. Roberts
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham;UK
| | - Paul Moss
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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30
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Bengtsson A, Andersson R, Ansari D. The actual 5-year survivors of pancreatic ductal adenocarcinoma based on real-world data. Sci Rep 2020; 10:16425. [PMID: 33009477 PMCID: PMC7532215 DOI: 10.1038/s41598-020-73525-y] [Citation(s) in RCA: 214] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 09/17/2020] [Indexed: 12/14/2022] Open
Abstract
Survival data for pancreatic cancer are usually based on actuarial calculations and actual long-term survival rates are rarely reported. Here we use population-level data from the Surveillance, Epidemiology, and End Results program for patients with microscopically confirmed pancreatic ductal adenocarcinoma diagnosed from 1975 to 2011. A total of 84,275 patients with at least 5 years of follow-up were evaluated (follow-up cutoff date: December 31, 2016). Actual 5-year survival for pancreatic cancer increased from 0.9% in 1975 to 4.2% in 2011 in patients of all stages (p < 0.001), while in surgically resected patients, it rose from 1.5% to 17.4% (p < 0.001). In non-resected patients, the actual 5-year survival remained unchanged over the same time period (0.8% vs 0.9%; p = 0.121). Multivariable analysis of surgically resected patients diagnosed in the recent time era (2004-2011) showed that age, gender, grade, tumour size, TNM-stage and chemotherapy were significant independent predictors of actual 5-year survival, while age, grade and TNM-stage were significant independent predictors in non-resected patients. However, unfavourable clinicopathological factors did not preclude long-term survival. Collectively, our findings indicate that actual 5-year survival for pancreatic cancer is still below 5% despite improvement of survival for the subset of patients undergoing surgical resection.
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Affiliation(s)
- Axel Bengtsson
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, 221 85, Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, 221 85, Lund, Sweden.
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31
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Kaleru T, Vankeshwaram VK, Maheshwary A, Mohite D, Khan S. Diabetes Mellitus in the Middle-Aged and Elderly Population (>45 Years) and Its Association With Pancreatic Cancer: An Updated Review. Cureus 2020; 12:e8884. [PMID: 32742851 PMCID: PMC7388804 DOI: 10.7759/cureus.8884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus (DM) and pancreatic cancer (PC) in the elderly are widely considered to be interrelated. New-onset diabetes (NOD) patients are considered a high-risk group for the development of PC within three years of diagnosis. We reviewed the literature to determine the pathophysiological association between DM and PC, which can help in the development of screening tests for early PC diagnosis in the elderly with NOD. We also studied the potential associations between them after pancreaticoduodenectomy (PD) or pancreatic resection. We collected studies published in the last five years in PubMed that are relevant to DM and PC in the elderly. We mainly focused on the pathophysiology and intracellular mechanisms involved between NOD and PC. We illustrated the clinical signs and immunological and metabolic biomarkers that can be used to diagnose early PC in the elderly with NOD. In the 34 studies we reviewed, five showed that long-term diabetes mellitus (LTDM) increases the risk of PC. Six studies showed that NOD in the elderly is an early sign of PC. Fourteen studies proposed that clinical signs and biomarker levels should be used to determine the high-risk risk group for PC among NOD patients. Six studies reported that NOD is associated with the worst outcomes postoperatively, and three studies showed that patients developed DM after pancreatic resection. LTDM is considered an independent risk factor for PC development in the elderly. NOD is a consequence and maybe the only early presenting sign of PC. Screening protocols and tests should be used in clinical practice to determine the proportion of NOD patients who should undergo further testing for early diagnosis of PC. DM and PC are also co-related postoperatively and patients should be monitored for impaired glucose levels, overall survival, and mortality.
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Affiliation(s)
- Thanmai Kaleru
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | | | - Ankush Maheshwary
- Neurology, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
- Medicine, Government Medical College, Amritsar, IND
| | - Divya Mohite
- Neurology, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Safeera Khan
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
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32
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Laurent-Badr Q, Barbe C, Brugel M, Hautefeuille V, Volet J, Grelet S, Desot E, Botsen D, Deguelte S, Pitta A, Abdelli N, Brasseur M, De Mestier L, Neuzillet C, Bouché O. Time intervals to diagnosis and chemotherapy do not influence survival outcome in patients with advanced pancreatic adenocarcinoma. Dig Liver Dis 2020; 52:658-667. [PMID: 32362489 DOI: 10.1016/j.dld.2020.03.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 02/23/2020] [Accepted: 03/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The effect of treatment delay on survival in pancreatic ductal adenocarcinoma (PDAC) remains unclear. AIMS This study aimed to assess the prognostic impact of time to diagnosis and chemotherapy in advanced PDAC and factors influencing the time intervals. METHODS advanced PDAC patients receiving chemotherapy in five centers in the decade 2007-2016 were included. Key time points during care pathway from clinical presentation to beginning of chemotherapy were retrospectively collected. Multivariate Cox proportional hazard model was performed. RESULTS A total of 409 patients were included (mean age 66.1 ± 10.3 years; 250 metastatic (61%); 139 received FOLFIRINOX chemotherapy (34%). The median overall survival (OS) was 7.2 months. The median times from first symptoms and from first specialist visit to the beginning of chemotherapy were respectively 100 days and 47 days. None of time intervals was significantly associated with OS. Significant prognostic factors were FOLFIRINOX chemotherapy (HR 0.6 [0.5-0.8]; P < 0.001), metastasis (HR 1.6 [1.3-2.0]; P = 0.001), WHO PS ≥ 2 (HR 1.6 [1.2-2.1]; P < 0.001) and acute pancreatitis as first symptom (HR 2.9 [1.7-4.9]; P < 0.001). Jaundice shortened time to diagnosis (P < 0.001). Acute pancreatitis (P < 0.001) and diabetes (P = 0.01) increased time to treatment. CONCLUSION Wait times from clinical presentation to beginning of chemotherapy do not influence survival in advanced PDAC.
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Affiliation(s)
- Q Laurent-Badr
- Digestive Oncology, Reims University Hospital, Reims, France.
| | - C Barbe
- Research and Public Health, Reims University Hospital, Reims, France
| | - M Brugel
- Digestive Oncology, Reims University Hospital, Reims, France
| | - V Hautefeuille
- Gastroenterology, Amiens-Picardie University Hospital, France
| | - J Volet
- Gastroenterology, Courlancy-Bezannes Clinic, Bezannes, France
| | - S Grelet
- Hollings Cancer Center, Medical University of South Carolina, Charleston, USA
| | - E Desot
- Medical Oncology, Institut de Cancérologie Godinot, Reims, France
| | - D Botsen
- Digestive Oncology, Reims University Hospital, Reims, France; Medical Oncology, Institut de Cancérologie Godinot, Reims, France
| | - S Deguelte
- General, Digestive and Endocrine Surgery, Reims University Hospital, Reims, France
| | - A Pitta
- Digestive Oncology, Reims University Hospital, Reims, France
| | - N Abdelli
- Gastroenterology, Châlons-en-Champagne Hospital, Châlons-en-Champagne, France
| | - M Brasseur
- Digestive Oncology, Reims University Hospital, Reims, France
| | - L De Mestier
- Gastroenterology and Pancreatology, Beaujon University Hospital, APHP, Clichy, France
| | - C Neuzillet
- Medical Oncology, Curie Institute, Versailles Saint Quentin University, Saint-Cloud, France
| | - O Bouché
- Digestive Oncology, Reims University Hospital, Reims, France
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Vundavilli H, Datta A, Sima C, Hua J, Lopes R, Bittner M. In Silico Design and Experimental Validation of Combination Therapy for Pancreatic Cancer. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2020; 17:1010-1018. [PMID: 30281473 DOI: 10.1109/tcbb.2018.2872573] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The number of deaths associated with Pancreatic Cancer has been on the rise in the United States making it an especially dreaded disease. The overall prognosis for pancreatic cancer patients continues to be grim because of the complexity of the disease at the molecular level involving the potential activation/inactivation of several diverse signaling pathways. In this paper, we first model the aberrant signaling in pancreatic cancer using a multi-fault Boolean Network. Thereafter, we theoretically evaluate the efficacy of different drug combinations by simulating this boolean network with drugs at the relevant intervention points and arrive at the most effective drug(s) to achieve cell death. The simulation results indicate that drug combinations containing Cryptotanshinone, a traditional Chinese herb derivative, result in considerably enhanced cell death. These in silico results are validated using wet lab experiments we carried out on Human Pancreatic Cancer (HPAC) cell lines.
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34
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Sagini MN, Klika KD, Hotz-Wagenblatt A, Zepp M, Berger MR. Lactosyl-sepharose binding proteins from pancreatic cancer cells show differential expression in primary and metastatic organs. Exp Biol Med (Maywood) 2020; 245:631-643. [PMID: 32131629 DOI: 10.1177/1535370220910691] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
In normal cells, glycan binding proteins mediate various cellular processes upon recognition and binding to respective ligands. In tumor cells, these proteins have been associated with metastasis. Lactosyl-sepharose binding proteins (LSBPs) were isolated and identified in a workflow involving lactosyl affinity chromatography and label-free quantification mass spectrometry (LFQ MS). A binding study with monosaccharides was performed by microscale thermophoresis and nuclear magnetic resonance spectroscopy. Influence of galactose on LSBPs’ binding to the lactosyl resin was investigated by competitive affinity chromatography followed by LFQ MS. An analysis of amino acids with sugar binding motifs was searched using bioinformatics tools. The expression profiles of these proteins at the mRNA level, as determined by a chip array from a pancreatic ductal adenocarcinoma (PDAC) liver metastasis model, were used for evaluating their potential role in cancer progression. Proteomics data and their respective genes were analyzed by MaxQuant and Ingenuity Pathway Analysis. In total, 1295 LSBPs were isolated and identified from Suit2-007 human pancreatic adenocarcinoma cells. Interaction studies revealed that these proteins exhibit low to moderate affinity for monosaccharide sugars. Some of these LSBPs even showed reduced affinity after calcium depletion. Among the isolated proteins were annexins and galectins in addition to other families, with no history of binding lactosyl residues. A subset of LSBPs exhibited differential profiles in the pancreas, liver, and lung environments. These modulations may be related to tumor progression. In conclusion, we show that PDAC cells contain LSBPs, a subset of which binds galactose with calcium dependency. The differential expression of these proteins in a rat model highlights their value for diagnosis and as potential drug targets for PDAC therapy. Future work will be required to validate these findings in patient samples.Impact statementInteraction of glycan binding proteins with aberrantly expressed glycans in tumor environment is crucial for metastasis. Here, we established a work flow for investigating the presence of a subset of these proteins in PDAC cells, which bind to a lactosyl-sepharose resin. The resin had been designed to isolate proteins with lectin-like properties. The corresponding lactosyl-sepharose binding proteins (LSBPs) show affinity for galactose and other monosaccharides. A subset of the LSBPs shows also calcium dependency. The importance of these proteins is highlighted by their differential expression profiles in PDAC cells growing in primary (pancreas) and metastatic (liver and lung) organ sites. Based on their affinity for the lactosyl-resin and monosaccharides, LSBPs hold potential for PDAC diagnosis and as drug targets. This work has set the stage for further investigation of the occurrence and the role of LSBPs in patient samples using the newly established workflow.
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Affiliation(s)
- Micah N Sagini
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Karel D Klika
- Molecular Structure Analysis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Agnes Hotz-Wagenblatt
- Genomics and Proteomics Core Facility, Bioinformatics-Husar Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Michael Zepp
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Martin R Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Majumder S, Raimondo M, Taylor WR, Yab TC, Berger CK, Dukek BA, Cao X, Foote PH, Wu CW, Devens ME, Mahoney DW, Smyrk TC, Pannala R, Chari ST, Vege SS, Topazian MD, Petersen BT, Levy MJ, Rajan E, Gleeson FC, Dayyeh BA, Nguyen CC, Faigel DO, Woodward TA, Wallace MB, Petersen G, Allawi HT, Lidgard GP, Kisiel JB, Ahlquist DA. Methylated DNA in Pancreatic Juice Distinguishes Patients With Pancreatic Cancer From Controls. Clin Gastroenterol Hepatol 2020; 18:676-683.e3. [PMID: 31323382 PMCID: PMC6984349 DOI: 10.1016/j.cgh.2019.07.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 07/10/2019] [Accepted: 07/12/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Precursors of pancreatic cancer arise in the ductal epithelium; markers exfoliated into pancreatic juice might be used to detect high-grade dysplasia (HGD) and cancer. Specific methylated DNA sequences in pancreatic tissue have been associated with adenocarcinoma. We analyzed these methylated DNA markers (MDMs) in pancreatic juice samples from patients with pancreatic ductal adenocarcinomas (PDACs) or intraductal papillary mucinous neoplasms (IPMNs) with HGD (cases), and assessed their ability to discriminate these patients from individuals without dysplasia or with IPMNs with low-grade dysplasia (controls). METHODS We obtained pancreatic juice samples from 38 patients (35 with biopsy-proven PDAC or pancreatic cystic lesions with invasive cancer and 3 with HGD) and 73 controls (32 with normal pancreas and 41 with benign disease), collected endoscopically from the duodenum after secretin administration from February 2015 through November 2016 at 3 medical centers. Samples were analyzed for the presence of 14 MDMs (in the genes NDRG4, BMP3, TBX15, C13orf18, PRKCB, CLEC11A, CD1D, ELMO1, IGF2BP1, RYR2, ADCY1, FER1L4, EMX1, and LRRC4), by quantitative allele-specific real-time target and signal amplification. We performed area under the receiver operating characteristic curve analyses to determine the ability of each marker, and panels of markers, to distinguish patients with HGD and cancer from controls. MDMs were combined to form a panel for detection using recursive partition trees. RESULTS We identified a group of 3 MDMs (at C13orf18, FER1L4, and BMP3) in pancreatic juice that distinguished cases from controls with an area under the receiver operating characteristic value of 0.90 (95% CI, 0.83-0.97). Using a specificity cut-off value of 86%, this group of MDMs distinguished patients with any stage of pancreatic cancer from controls with 83% sensitivity (95% CI, 66%-93%) and identified patients with stage I or II PDAC or IPMN with HGD with 80% sensitivity (95% CI, 56%-95%). CONCLUSIONS We identified a group of 3 MDMs in pancreatic juice that identify patients with pancreatic cancer with an area under the receiver operating characteristic value of 0.90, including patients with early stage disease or advanced precancer. These DNA methylation patterns might be included in algorithms for early detection of pancreatic cancer, especially in high-risk cohorts. Further optimization and clinical studies are needed.
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Affiliation(s)
- Shounak Majumder
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Massimo Raimondo
- Division of Gastroenterology & Hepatology Mayo Clinic Jacksonville, FL
| | - William R. Taylor
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Tracy C. Yab
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Calise K. Berger
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Brian A. Dukek
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Xiaoming Cao
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Patrick H. Foote
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Chung Wah Wu
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Mary E. Devens
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Douglas W. Mahoney
- Department of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN
| | - Thomas C. Smyrk
- Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN
| | - Rahul Pannala
- Division of Gastroenterology & Hepatology, Mayo Clinic Scottsdale, AZ
| | - Suresh T. Chari
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | | | - Mark D. Topazian
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Bret T. Petersen
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Michael J. Levy
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Elizabeth Rajan
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Ferga C. Gleeson
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Barham Abu Dayyeh
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Cuong C. Nguyen
- Division of Gastroenterology & Hepatology, Mayo Clinic Scottsdale, AZ
| | - Douglas O. Faigel
- Division of Gastroenterology & Hepatology, Mayo Clinic Scottsdale, AZ
| | | | | | - Gloria Petersen
- Department of Health Sciences Research Mayo Clinic, Rochester, MN
| | | | | | - John B. Kisiel
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - David A. Ahlquist
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
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Expression of Monocarboxylate Transporter 1 Is Associated With Better Prognosis and Reduced Nodal Metastasis in Pancreatic Ductal Adenocarcinoma. Pancreas 2019; 48:1102-1110. [PMID: 31404019 DOI: 10.1097/mpa.0000000000001369] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Because lactate is believed to support tumor growth, monocarboxylate transporters (MCTs), which transport lactate, have been investigated in multiple tumors. However, the significance of MCTs in pancreatic cancer is unclear. METHODS A retrospective survey was conducted on 240 patients who underwent surgical resection for pancreatic ductal adenocarcinoma without preoperative treatment. The expression of MCT1, MCT2, MCT3, MCT4, and the glucose transporter 1 (GLUT1) was assessed in tumor cells and cancer-associated fibroblasts (CAFs) by tissue microarrays and immunohistochemistry. The impact of their expression on patient outcome and clinicopathological characteristics was also analyzed. RESULTS In tumor cells, MCT1, MCT2, MCT3, MCT4, and GLUT1 were detected in 52 (22%), 31 (13%), 149 (62%), 204 (85%), and 235 (98%) cases, respectively. In CAFs, MCT2, MCT4, and GLUT1 were detected in 9 (3.8%), 178 (74%), and 36 (15%) cases, respectively. In tumor cells, MCT1 expression was associated with extended overall and progression-free survival and decreased nodal metastasis. Conversely, MCT4 expression in CAFs was associated with shortened survival. CONCLUSIONS In tumor cells, MCT1 expression is associated with better prognosis and reduced nodal metastasis in pancreatic cancer, contrary to findings of past in vitro studies. Conversely, MCT4 expression in CAFs is indicative of worse prognosis.
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37
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Mueller AM, Meier CR, Jick SS, Schneider C. Weight change and blood glucose concentration as markers for pancreatic cancer in subjects with new-onset diabetes mellitus: A matched case-control study. Pancreatology 2019; 19:578-586. [PMID: 30952448 DOI: 10.1016/j.pan.2019.03.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/18/2019] [Accepted: 03/22/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To evaluate the potential of blood glucose levels and weight change before the onset of diabetes as predictors of pancreatic cancer among subjects with new-onset diabetes, that is, cancer-related diabetes versus normal type 2 diabetes. METHODS We conducted a case-control study among subjects with new diabetes in the United Kingdom-based Clinical Practice Research Datalink. Cases were pancreatic cancer subjects with diabetes for ≤2 years before the cancer diagnosis (i.e., cancer-related diabetes). Controls were cancer-free, type 2 diabetic subjects matched to cases on age, sex, and diabetes duration. We calculated adjusted odds ratios (aORs) for pancreatic cancer as a function of both weight change and blood glucose before the onset of diabetes. RESULTS Weight loss of 10.0%-14.9% at diabetes onset was associated with an aOR for pancreatic cancer of 3.58 (95% CI 2.31-5.54), loss of ≥15.0%, with an aOR of 4.56 (95% CI 2.82-7.36), compared with stable weight. Blood glucose levels of ≤5.1 mmol/L or 5.2-5.6 mmol/L before diabetes onset were associated with an increased risk of a pancreatic cancer diagnosis, with aORs of 2.42 (95% CI 1.60-3.66) and 2.20 (95% CI 1.45-3.35), respectively, when compared with blood glucose levels ≥6.3 mmol/L within >2-3 years before cancer detection. CONCLUSIONS Weight loss as well as blood glucose levels in the normal range (and thus rapid development of hyperglycemia) before diabetes onset may be predictive of pancreatic cancer-related diabetes and may help target which subjects with new diabetes to refer for pancreatic cancer screening examinations.
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Affiliation(s)
- Alexandra M Mueller
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Basel, Switzerland
| | - Christoph R Meier
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Basel, Switzerland; Boston Collaborative Drug Surveillance Program, Lexington, MA, United States.
| | - Susan S Jick
- Boston Collaborative Drug Surveillance Program, Lexington, MA, United States; Boston University School of Public Health, Boston, MA, United States
| | - Cornelia Schneider
- Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Hospital Pharmacy, University Hospital Basel, Basel, Switzerland
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Honda K, Katzke VA, Hüsing A, Okaya S, Shoji H, Onidani K, Olsen A, Tjønneland A, Overvad K, Weiderpass E, Vineis P, Muller D, Tsilidis K, Palli D, Pala V, Tumino R, Naccarati A, Panico S, Aleksandrova K, Boeing H, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Lagiou P, Khaw KT, Wareham N, Travis RC, Merino S, Duell EJ, Rodríguez-Barranco M, Chirlaque MD, Barricarte A, Rebours V, Boutron-Ruault MC, Romana Mancini F, Brennan P, Scelo G, Manjer J, Sund M, Öhlund D, Canzian F, Kaaks R. CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation. Int J Cancer 2019; 144:1877-1887. [PMID: 30259989 PMCID: PMC6760974 DOI: 10.1002/ijc.31900] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 07/06/2018] [Accepted: 07/13/2018] [Indexed: 12/24/2022]
Abstract
Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.
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Affiliation(s)
- Kazufumi Honda
- Department of Biomarker for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan
- Japan Agency for Medical Research and Development (AMED) CREST, Tokyo, Japan
| | - Verena A Katzke
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anika Hüsing
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Shinobu Okaya
- Department of Biomarker for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan
| | - Hirokazu Shoji
- Department of Biomarker for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Kaoru Onidani
- Department of Biomarker for Early Detection of Cancer, National Cancer Center Research Institute, Tokyo, Japan
| | - Anja Olsen
- Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Anne Tjønneland
- Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Kim Overvad
- Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
- Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - Paolo Vineis
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom
| | - David Muller
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom
| | - Kostas Tsilidis
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
| | - Valeria Pala
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Rosario Tumino
- Cancer Registry and Histopathology Unit, "Civic - M.P. Arezzo" Hospital, Ragusa, Italy
| | - Alessio Naccarati
- Department of Molecular and Genetic Epidemiology, IIGM - Italian Institute for Genomic Medicine, Torino, Italy
| | - Salvatore Panico
- Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
| | - Krasimira Aleksandrova
- Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
| | - H Bas Bueno-de-Mesquita
- Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom
- Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Petra H Peeters
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom
| | - Antonia Trichopoulou
- Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, School of Medicine, WHO Collaborating Center for Nutrition and Health
| | - Pagona Lagiou
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Kay-Tee Khaw
- Cancer Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
| | - Nick Wareham
- MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Susana Merino
- Public Health Directorate, Asturias, Spain, Acknowledgment of funds: Regional Government of Asturias
| | - Eric J Duell
- PanC4 Consortium, Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Miguel Rodríguez-Barranco
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
- CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain
| | - María Dolores Chirlaque
- Department of Epidemiology, Murcia Regional Health Council, CIBER Epidemiología y Salud Pública (CIBERESP), Spain, Ronda de Levante, Murcia, Spain
| | - Aurelio Barricarte
- CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain
- Navarra Public Health Institute, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Vinciane Rebours
- Pancreatology Unit, Beaujon Hospital, Clichy, France
- INSERM - UMR 1149, University Paris 7, Paris, France
| | - Marie-Chiristine Boutron-Ruault
- CESP, INSERM U1018, Univ. Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France
- Lifestyle, Genes and Health: Integrative Trans-Generational Epidemiology, Gustave Roussy, Villejuif, France
| | - Francesca Romana Mancini
- INSERM - UMR 1149, University Paris 7, Paris, France
- CESP, INSERM U1018, Univ. Paris-Sud, UVSQ, Université Paris-Saclay, Villejuif, France
| | - Paul Brennan
- Section of Genetics, International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France
| | - Ghislaine Scelo
- Section of Genetics, International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France
| | - Jonas Manjer
- Department of Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - Malin Sund
- Department of Surgical and Preoperative Sciences, Umeå University, Umeå, Sweden
| | - Daniel Öhlund
- Department of Radiation Sciences and Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Federico Canzian
- Genomic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Stoffel EM, McKernin SE, Brand R, Canto M, Goggins M, Moravek C, Nagarajan A, Petersen GM, Simeone DM, Yurgelun M, Khorana AA. Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol 2019; 37:153-164. [DOI: 10.1200/jco.18.01489] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO’s membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members’ curated files. Provisional Clinical Opinion All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .
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Affiliation(s)
| | | | | | | | | | | | - Arun Nagarajan
- Taussig Cancer Institute and Case Comprehensive Cancer Center, Cleveland Clinic, Cleveland, OH
| | | | | | | | - Alok A. Khorana
- Taussig Cancer Institute and Case Comprehensive Cancer Center, Cleveland Clinic, Cleveland, OH
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Abstract
PURPOSE OF REVIEW The relationship between pancreatic ductal adenocarcinoma (PDAC) and diabetes mellitus (DM) is complex. We reviewed the recent medical literature regarding the effect of anti-diabetic medication on PDAC risk and survival, risk of PDAC in DM, and role of DM in early detection of PDAC. RECENT FINDINGS Studies report that while some anti-diabetic medications (e.g., metformin) may decrease the risk of PDAC, others (insulin, sulfonylureas and incretin-based therapies) may increase the risk. However, these observations may be subject to protopathic biases. Metformin's anti-tumor activity may have influence overall survival of PDAC, but epidemiological reports have largely been inconsistent to defend these findings due to heterogeneous methodologies. There is congruent data to support the association between DM and PDAC, with an inverse relationship to DM duration. Older subjects with new-onset DM are the only known high-risk group for PDAC, and strategy using this group for early detection has led to development of clinical risk prediction models that define a very high-risk PDAC group. Role of anti-diabetic medication in PDAC risk modification or survival is controversial. With successful efforts to distinguish type 2-DM from PDAC-DM using risk-stratifying models, there is an opportunity to initiate screening protocols for early detection of PDAC in a sub-set of DM subjects.
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Affiliation(s)
- Ayush Sharma
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Sciences, 200 First St SW, Rochester, MN, 55905, USA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Sciences, 200 First St SW, Rochester, MN, 55905, USA.
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41
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Garcia-Carbonero N, Li W, Cabeza-Morales M, Martinez-Useros J, Garcia-Foncillas J. New Hope for Pancreatic Ductal Adenocarcinoma Treatment Targeting Endoplasmic Reticulum Stress Response: A Systematic Review. Int J Mol Sci 2018; 19:E2468. [PMID: 30134550 PMCID: PMC6165247 DOI: 10.3390/ijms19092468] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 08/10/2018] [Accepted: 08/18/2018] [Indexed: 12/28/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical resection when these tumours are detected at an early stage, this cancer is usually asymptomatic, and disease only becomes apparent after metastasis. Several risk factors are associated with this disease, the most relevant being chronic pancreatitis, diabetes, tobacco and alcohol intake, cadmium, arsenic and lead exposure, certain infectious diseases, and the mutational status of some genes associated to a familial component. PDAC incidence has increased in recent decades, and there are few alternatives for chemotherapeutic treatment. Endoplasmic reticulum (ER) stress factors such as GRP78/BiP (78 kDa glucose-regulated protein), ATF6α (activating transcription factor 6 isoform α), IRE1α (inositol-requiring enzyme 1 isoform α), and PERK (protein kinase RNA-like endoplasmic reticulum kinase) activate the transcription of several genes involved in both survival and apoptosis. Some of these factors aid in inducing a non-proliferative state in cancer called dormancy. Modulation of endoplasmic reticulum stress could induce dormancy of tumour cells, thus prolonging patient survival. In this systematic review, we have compiled relevant results concerning those endoplasmic reticulum stress factors involved in PDAC, and we have analysed the mechanism of dormancy associated to endoplasmic reticulum stress and its potential use as a chemotherapeutic target against PDAC.
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MESH Headings
- Activating Transcription Factor 6/genetics
- Activating Transcription Factor 6/metabolism
- Animals
- Antibodies/pharmacology
- Carcinoma, Pancreatic Ductal/etiology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/therapy
- Communicable Diseases/complications
- Communicable Diseases/genetics
- Communicable Diseases/metabolism
- Communicable Diseases/pathology
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/pharmacology
- Diabetes Complications/genetics
- Diabetes Complications/metabolism
- Diabetes Complications/pathology
- Disease Models, Animal
- Endoplasmic Reticulum Chaperone BiP
- Endoplasmic Reticulum Stress/drug effects
- Endoplasmic Reticulum Stress/genetics
- Endoribonucleases/genetics
- Endoribonucleases/metabolism
- Gene Expression Regulation
- Heat-Shock Proteins/antagonists & inhibitors
- Heat-Shock Proteins/genetics
- Heat-Shock Proteins/metabolism
- Humans
- Pancreatic Neoplasms/etiology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/therapy
- Pancreatitis, Chronic/complications
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Risk Factors
- Sulfones/pharmacology
- eIF-2 Kinase/genetics
- eIF-2 Kinase/metabolism
- Gemcitabine
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Affiliation(s)
- Nuria Garcia-Carbonero
- Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-UAM, Avda Reyes Catolicos 2, 28040 Madrid, Spain.
| | - Weiyao Li
- Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-UAM, Avda Reyes Catolicos 2, 28040 Madrid, Spain.
| | - Marticela Cabeza-Morales
- Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-UAM, Avda Reyes Catolicos 2, 28040 Madrid, Spain.
| | - Javier Martinez-Useros
- Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-UAM, Avda Reyes Catolicos 2, 28040 Madrid, Spain.
| | - Jesus Garcia-Foncillas
- Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-UAM, Avda Reyes Catolicos 2, 28040 Madrid, Spain.
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The Potential of Glycemic Control and Body Weight Change as Early Markers for Pancreatic Cancer in Patients With Long-standing Diabetes Mellitus: A Case-Control Study. Pancreas 2018; 47:807-815. [PMID: 29975346 DOI: 10.1097/mpa.0000000000001085] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The aim of this study was to characterize the role of glycemic control and weight change as markers for pancreatic cancer (PaC) in patients with long-standing diabetes. METHODS We conducted case-control analyses in patients with long-standing diabetes (>2 years) in the United Kingdom-based Clinical Practice Research Datalink. Cases were patients with PaC matched to control subjects on variables including age, sex, and diabetes duration. We compared glycated hemoglobin (HbA1c) levels, blood glucose levels, and weight change before cancer detection (matched date) between cases and control subjects to assess associations between the potential markers and PaC. RESULTS Cases were more likely than control subjects to have high HbA1c levels. The adjusted odds ratio (aOR) was 4.94 (95% confidence interval [CI], 3.52-6.94) for HbA1c of 64.0 mmol/mol or greater compared with HbA1c of 47.5 mmol/mol or less within 6 months before cancer detection and within >1 to 2 years, 2.66 (95% CI, 2.00-3.54). Weight loss was also more common in cases, with an aOR of 15.40 (95% CI, 10.65-22.26) for loss of 15.0% body weight or greater compared with stable weight. The aOR for patients with both weight loss of 15.0% or greater and high HbA1c at 2 years or less before diagnosis was 60.97 (95% CI, 35.87-103.65), compared with patients with neither. CONCLUSIONS Poor glycemic control and weight loss, particularly in combination, may be useful early markers for PaC in patients with long-standing diabetes.
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Matters GL, Harms JF. Utilizing Peptide Ligand GPCRs to Image and Treat Pancreatic Cancer. Biomedicines 2018; 6:biomedicines6020065. [PMID: 29865257 PMCID: PMC6027158 DOI: 10.3390/biomedicines6020065] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 05/28/2018] [Indexed: 12/18/2022] Open
Abstract
It is estimated that early detection of pancreatic ductal adenocarcinoma (PDAC) could increase long-term patient survival by as much as 30% to 40% (Seufferlein, T. et al., Nat. Rev. Gastroenterol. Hepatol.2016, 13, 74–75). There is an unmet need for reagents that can reliably identify early cancerous or precancerous lesions through various imaging modalities or could be employed to deliver anticancer treatments specifically to tumor cells. However, to date, many PDAC tumor-targeting strategies lack selectivity and are unable to discriminate between tumor and nontumor cells, causing off-target effects or unclear diagnoses. Although a variety of approaches have been taken to identify tumor-targeting reagents that can effectively direct therapeutics or imaging agents to cancer cells (Liu, D. et al., J. Controlled Release2015, 219, 632–643), translating these reagents into clinical practice has been limited, and it remains an area open to new methodologies and reagents (O’Connor, J.P. et al., Nat. Rev. Clin. Oncol. 2017, 14, 169–186). G protein–coupled receptors (GPCRs), which are key target proteins for drug discovery and comprise a large proportion of currently marketed therapeutics, hold significant promise for tumor imaging and targeted treatment, particularly for pancreatic cancer.
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Affiliation(s)
- Gail L Matters
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
| | - John F Harms
- Department of Biological Sciences, Messiah College, Mechanicsburg, PA 17055, USA.
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Sánchez-García J, Candanedo-González F, Félix-Félix AK, Sánchez-Ramírez D, Medrano-Guzmán R, Quintana-Quintana M, Baas-Cabrera YB, Flores-Figueroa E. Retrospective cohort of pancreatic and Vater ampullary adenocarcinoma from a reference center in Mexico. Ann Med Surg (Lond) 2018; 30:7-12. [PMID: 29707208 PMCID: PMC5918165 DOI: 10.1016/j.amsu.2018.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 03/25/2018] [Accepted: 04/03/2018] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) and ampulla of Vater adenocarcinomas (AVAC) are periampullary tumors. These tumors have overlapping symptoms and a common treatment, but present differences in their survival and biology. No recent studies in Mexico have been published that describe the clinicopathological characteristics of these tumors. Therefore, the aim of this study was to describe the clinicopathological characteristics of PDAC and AVAC in patients at a reference center in Mexico. METHODS A retrospective cohort of patients with PDAC or AVAC was analyzed at our institution (July 2007 to June 2016). Inferential analysis of the clinical data was performed with Student's t-test or a χ2 test with odds ratios (OR) and confidence intervals (CI), depending on the variables. Overall survival was compared using Kaplan-Meier curves with log-rank p values. RESULTS Forty patients with PDAC and 76 with AVAC were analyzed, including 77 females and 39 males with a mean age of 60.6 years and a mean evolution time of 5.7 months. PDAC patients had more abdominal pain, a larger tumor size and more advanced stages than AVAC patients. In contrast, AVAC patients had more jaundice, a higher percentage of complete resections and higher overall survival. Up to 70% of patients were overweight. PDAC cohort included a higher proportion of smokers. CONCLUSIONS Our cohort was slightly younger, had a larger percentage of females, and a greater percentage of obese patients than those in many international reports. A high proportion of PDAC patients are diagnosed in advanced stages and have a low likelihood of resectability.
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Affiliation(s)
| | | | | | | | | | - Miguel Quintana-Quintana
- Medical Oncology Service, Oncology Hospital, National Medical Center Century XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Yair Benjamín Baas-Cabrera
- Medical Oncology Service, Oncology Hospital, National Medical Center Century XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
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Unger K, Mehta KY, Kaur P, Wang Y, Menon SS, Jain SK, Moonjelly RA, Suman S, Datta K, Singh R, Fogel P, Cheema AK. Metabolomics based predictive classifier for early detection of pancreatic ductal adenocarcinoma. Oncotarget 2018; 9:23078-23090. [PMID: 29796173 PMCID: PMC5955422 DOI: 10.18632/oncotarget.25212] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 04/06/2018] [Indexed: 12/13/2022] Open
Abstract
The availability of robust classification algorithms for the identification of high risk individuals with resectable disease is critical to improving early detection strategies and ultimately increasing survival rates in PC. We leveraged high quality biospecimens with extensive clinical annotations from patients that received treatment at the Medstar-Georgetown University hospital. We used a high resolution mass spectrometry based global tissue profiling approach in conjunction with multivariate analysis for developing a classification algorithm that would predict early stage PC with high accuracy. The candidate biomarkers were annotated using tandem mass spectrometry. We delineated a six metabolite panel that could discriminate early stage PDAC from benign pancreatic disease with >95% accuracy of classification (Specificity = 0.85, Sensitivity = 0.9). Subsequently, we used multiple reaction monitoring mass spectrometry for evaluation of this panel in plasma samples obtained from the same patients. The pattern of expression of these metabolites in plasma was found to be discordant as compared to that in tissue. Taken together, our results show the value of using a metabolomics approach for developing highly predictive panels for classification of early stage PDAC. Future investigations will likely lead to the development of validated biomarker panels with potential for clinical translation in conjunction with CA-19-9 and/or other biomarkers.
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Affiliation(s)
- Keith Unger
- MedStar Georgetown University Hospital, Washington, DC, United States of America
| | - Khyati Y Mehta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Prabhjit Kaur
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Yiwen Wang
- Department of Biostatistics and Biomathematics, Georgetown University Medical Center, Washington, DC, United States of America
| | - Smrithi S Menon
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Shreyans K Jain
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Rose A Moonjelly
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Shubhankar Suman
- Departments of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, United States of America
| | - Kamal Datta
- Departments of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, United States of America
| | - Rajbir Singh
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Paul Fogel
- Unité MéDIAN, UMR CNRS 6237 MEDYC, Université de Reims, Reims, France
| | - Amrita K Cheema
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.,Departments of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, United States of America
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Habartová L, Bunganič B, Tatarkovič M, Zavoral M, Vondroušová J, Syslová K, Setnička V. Chiroptical spectroscopy and metabolomics for blood-based sensing of pancreatic cancer. Chirality 2018; 30:581-591. [DOI: 10.1002/chir.22834] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/23/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Lucie Habartová
- Department of Analytical Chemistry; University of Chemistry and Technology Prague; Prague 6 Czech Republic
| | - Bohuš Bunganič
- Department of Internal Medicine, First Faculty of Medicine, Military University Hospital; Charles University; Prague 6 Czech Republic
| | - Michal Tatarkovič
- Department of Analytical Chemistry; University of Chemistry and Technology Prague; Prague 6 Czech Republic
| | - Miroslav Zavoral
- Department of Internal Medicine, First Faculty of Medicine, Military University Hospital; Charles University; Prague 6 Czech Republic
| | - Jana Vondroušová
- Department of Organic Technology; University of Chemistry and Technology Prague; Prague 6 Czech Republic
| | - Kamila Syslová
- Department of Organic Technology; University of Chemistry and Technology Prague; Prague 6 Czech Republic
| | - Vladimír Setnička
- Department of Analytical Chemistry; University of Chemistry and Technology Prague; Prague 6 Czech Republic
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47
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Abstract
A diagnosis of pancreatic cancer is devastating owing to its poor prognosis, with a 5-year survival rate of only 9%. Currently, most individuals are diagnosed at a late stage when treatment options are limited. Early detection of pancreatic cancer provides the greatest hope for making substantial improvements in survival. The Kenner Family Research Fund in partnership with the American Pancreatic Association has sponsored a series of fora to stimulate discussion and collaboration on early detection of pancreatic cancer. At the first forum in 2014, "Early Detection of Sporadic Pancreatic Cancer Summit Conference," a strategic plan was set forth by an international group of interdisciplinary scientific representatives and subsequently The Strategic Map for Innovation was generated. The current conference report is the third forum in the series, "Early Detection of Pancreatic Cancer: The Role of Industry in the Development of Biomarkers," which was held in Boston, Massachusetts, on October 27, 2016. This report provides an overview of examples of innovative initiatives by industry and confirms the critical need for collaboration among industry, government, research institutions, and advocacy groups in order to make pancreatic cancer more easily detectable in its earlier stages, when it is more treatable.
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48
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Bujanda L, Herreros-Villanueva M. Pancreatic Cancer in Lynch Syndrome Patients. J Cancer 2017; 8:3667-3674. [PMID: 29151953 PMCID: PMC5688919 DOI: 10.7150/jca.20750] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 08/23/2017] [Indexed: 02/06/2023] Open
Abstract
Although colorectal cancer (CRC) is the most common cancer type in Lynch syndrome (LS) families, patients have also increased lifetime risk of other types of tumors. The accumulated risk of pancreatic cancer (PC) in LS patients is around 3.7% and developed tumors often present a characteristically medullary appearance with prominent lymphocytic infiltration. LS patients are considered in high risk for PC development as they present 8.6-fold increase compared with the general population. Here we review PC cases reported in LS patients and current management guidelines. Literature data show that LS is clearly associated with PC and recent publications also demonstrated a connection with pancreatic neoplasic precursor lesions such as intraductal papillary mucinous neoplasms (IPMN) in these patients. While screening techniques are well established for CRC detection, clear strategies are not yet uniform for PC. Magnetic resonance imaging (MRI) and/or endoscopic ultrasound every 1-2 years in MMR mutation carriers with PC in a first or second-degree relative is recommended. Better pancreatic cancer detection strategies should be urgently defined due to the importance of early diagnosis in this disease.
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Affiliation(s)
- Luis Bujanda
- Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco UPV/EHU, San Sebastián 20014, Spain
| | - Marta Herreros-Villanueva
- Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco UPV/EHU, San Sebastián 20014, Spain.,Faculty of Life Sciences, Universidad Isabel I, Spain
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49
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Bekkali NLH, Oppong KW. Pancreatic ductal adenocarcinoma epidemiology and risk assessment: Could we prevent? Possibility for an early diagnosis. Endosc Ultrasound 2017; 6:S58-S61. [PMID: 29387690 PMCID: PMC5774073 DOI: 10.4103/eus.eus_60_17] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Noor L H Bekkali
- Department of Gastroenterology and HPB Unit Freeman Hospital, Newcastle upon Tyne, UK.,Department of Gastroenterology, Freeman Hospital, Newcastle upon Tyne, UK
| | - Kofi W Oppong
- Department of Gastroenterology and HPB Unit Freeman Hospital, Newcastle upon Tyne, UK.,Department of Gastroenterology, Freeman Hospital, Newcastle upon Tyne, UK
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