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Zhu W, Chen L, Aphinyanaphongs Y, Kastrinos F, Simeone DM, Pochapin M, Stender C, Razavian N, Gonda TA. Identification of patients at risk for pancreatic cancer in a 3-year timeframe based on machine learning algorithms. Sci Rep 2025; 15:11697. [PMID: 40188106 PMCID: PMC11972345 DOI: 10.1038/s41598-025-89607-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 02/06/2025] [Indexed: 04/07/2025] Open
Abstract
Early detection of pancreatic cancer (PC) remains challenging largely due to the low population incidence and few known risk factors. However, screening in at-risk populations and detection of early cancer has the potential to significantly alter survival. In this study, we aim to develop a predictive model to identify patients at risk for developing new-onset PC at two and a half to three year time frame. We used the Electronic Health Records (EHR) of a large medical system from 2000 to 2021 (N = 537,410). The EHR data analyzed in this work consists of patients' demographic information, diagnosis records, and lab values, which are used to identify patients who were diagnosed with pancreatic cancer and the risk factors used in the machine learning algorithm for prediction. We identified 73 risk factors of pancreatic cancer with the Phenome-wide Association Study (PheWAS) on a matched case-control cohort. Based on them, we built a large-scale machine learning algorithm based on EHR. A temporally stratified validation based on patients not included in any stage of the training of the model was performed. This model showed an AUROC at 0.742 [0.727, 0.757] which was similar in both the general population and in a subset of the population who has had prior cross-sectional imaging. The rate of diagnosis of pancreatic cancer in those in the top 1 percentile of the risk score was 6 folds higher than the general population. Our model leverages data extracted from a 6-month window of time in the electronic health record to identify patients at nearly sixfold higher than baseline risk of developing pancreatic cancer 2.5-3 years from evaluation. This approach offers an opportunity to define an enriched population entirely based on static data, where current screening may be recommended.
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Affiliation(s)
- Weicheng Zhu
- Center for Data Science, New York University, New York, NY, USA
| | - Long Chen
- Center for Data Science, New York University, New York, NY, USA
| | - Yindalon Aphinyanaphongs
- Department of Population Health, New York University Grossman School of Medicine, 227 East 30th Street, 6th Floor, New York, NY, 10016, USA
| | - Fay Kastrinos
- Department of Medicine, Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA
| | - Diane M Simeone
- Moores Cancer Center, UC San Diego Health, San Diego, CA, USA
| | - Mark Pochapin
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University, 240 East 38th Street, 23rd Floor, New York, NY, 10016, USA
| | - Cody Stender
- Department of Surgery, New York University, New York, NY, USA
| | - Narges Razavian
- Department of Population Health, New York University Grossman School of Medicine, 227 East 30th Street, 6th Floor, New York, NY, 10016, USA.
| | - Tamas A Gonda
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University, 240 East 38th Street, 23rd Floor, New York, NY, 10016, USA.
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Walsh RM, Ambrose J, Jack JL, Eades AE, Bye BA, Tannus Ruckert M, Messaggio F, Olou AA, Chalise P, Pei D, VanSaun MN. Depletion of tumor-derived CXCL5 improves T cell infiltration and anti-PD-1 therapy response in an obese model of pancreatic cancer. J Immunother Cancer 2025; 13:e010057. [PMID: 40121029 PMCID: PMC11931939 DOI: 10.1136/jitc-2024-010057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 03/10/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. CXC-ligands are a family of cytokines responsible for stimulating these receptors; while typically secreted by activated immune cells, fibroblasts, and even adipocytes, they are also secreted by immune-evasive cancer cells. CXC-ligand release is known to occur in response to inflammatory stimuli. Adipose tissue is an endocrine organ and a source of inflammatory signaling peptides. Importantly, adipose-derived cytokines and chemokines are implicated as potential drivers of tumor cell immune evasion; cumulatively, these findings suggest that targeting CXC-ligands may be beneficial in the context of obesity. METHODS RNA-sequencing of human PDAC cell lines was used to assess influences of adipose conditioned media on the cancer cell transcriptome. The adipose-induced secretome of PDAC cells was validated with ELISA for induction of CXCL5 secretion. Human tissue data from CPTAC was used to correlate IL-1β and TNF expression with both CXCL5 mRNA and protein levels. CRISPR-Cas9 was used to knockout CXCL5 from a murine PDAC KPC cell line to assess orthotopic tumor studies in syngeneic, diet-induced obese mice. Flow cytometry and immunohistochemistry were used to compare the immune profiles between tumors with or without CXCL5. Mice-bearing CXCL5 competent or deficient tumors were monitored for differential tumor size in response to anti-PD-1 immune checkpoint blockade therapy. RESULTS Human adipose tissue conditioned media stimulates CXCL5 secretion from PDAC cells via either IL-1β or TNF; neutralization of both is required to significantly block the release of CXCL5 from tumor cells. Ablation of CXCL5 from tumors promoted an enriched immune phenotype with an unanticipatedly increased number of exhausted CD8 T cells. Application of anti-PD-1 treatment to control tumors failed to alter tumor growth, yet treatment of CXCL5-deficient tumors showed response by significantly diminished tumor mass. CONCLUSIONS In summary, our findings show that both TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro, which correlates with expression in patient data. CXCL5 depletion in vivo alone is sufficient to promote T cell infiltration into tumors, increasing efficacy and requiring checkpoint blockade inhibition to alleviate tumor burden.
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Affiliation(s)
| | | | | | | | | | | | - Fanuel Messaggio
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | - Prabhakar Chalise
- Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- The University of Kansas Cancer Center, Kansas City, Kansas, USA
| | - Dong Pei
- Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- The University of Kansas Cancer Center, Kansas City, Kansas, USA
| | - Michael N VanSaun
- Cancer Biology, KUMC, Kansas City, Kansas, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
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3
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Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [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: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
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Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Ibrahim RM, Solanki S, Qiao W, Hwang H, Singh BS, Cazacu IM, Saftoiu A, Katz MHG, Kim MP, McAllister F, Bhutani MS. Fatty pancreas on EUS: Risk factors, correlation with CT/MRI, and implications for pancreatic cancer screening. Endosc Ultrasound 2025; 14:13-19. [PMID: 40151596 PMCID: PMC11939939 DOI: 10.1097/eus.0000000000000109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 01/02/2025] [Indexed: 03/29/2025] Open
Abstract
Background and Objectives Fatty pancreas (FP), traditionally perceived as a benign finding, has been undergoing scrutiny lately due to growing evidence linking it to various disease states, including increased risk for pancreatic cancer (PC). Methods A retrospective study of patients who underwent EUS at a single institution from August 2007 to October 2023, conducted by one endosonographer with more than 25 years of experience. Focusing on individuals identified with FP during EUS, we compared these findings with corresponding findings on computed tomography/magnetic resonance imaging (CT/MRI) conducted within 3 months or 1 year prior to or following EUS. Results Ninety-one patients were included and identified as having FP on their EUS exams. The most common indication for EUS was PC screening in high-risk patients (35.16%). At the time of conducting EUS, 65.93% of patients had a body mass index (BMI) ≥30, 63.73% had hypertension, and 32.96% had type 2 diabetes mellitus (DM). Of the 91 patients, 70 had CT or MRI done within 3 months of the EUS date, and only 15 (21.43%) had FP reported on imaging. All 91 patients had CT or MRI within 1 year, and only 16 (17.58%) had FP reported on imaging. Conclusion Only 21.43% of patients had FP on their CT/MRI within 3 months despite EUS findings, suggesting either lower accuracy of CT/MRI compared to EUS in identifying FP or potential underreporting in a real-world setting, even in a tertiary care center. This discrepancy in reporting is noteworthy considering FP's role as a potential precursor to several important conditions and promoting pancreatic carcinogenesis pathways.
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Affiliation(s)
- Ramez M. Ibrahim
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shantanu Solanki
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei Qiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hyunsoo Hwang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ben S. Singh
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Irina M. Cazacu
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Adrian Saftoiu
- Department of Gastroenterology and Hepatology, Elias Emergency University Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
| | - Matthew H. G. Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael P. Kim
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manoop S. Bhutani
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Kim MS, Lee I, Natarajan P, Do R, Kwon Y, Shin JI, Solmi M, Kim JY, Won HH, Park S. Integration of observational and causal evidence for the association between adiposity and 17 gastrointestinal outcomes: An umbrella review and meta-analysis. Obes Rev 2024; 25:e13823. [PMID: 39233338 DOI: 10.1111/obr.13823] [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: 11/08/2022] [Revised: 07/10/2024] [Accepted: 08/08/2024] [Indexed: 09/06/2024]
Abstract
We systematically reviewed observational and Mendelian randomization (MR) articles that evaluated the association between obesity and 17 gastrointestinal (GI) diseases to integrate causal and observational evidence. A total of 594 observational studies from 26 systematic reviews and meta-analyses and nine MR articles were included. For every 5 kg/m2 increase in body mass index (BMI), there was an increased risk of GI diseases ranging from 2% for rectal cancer (relative risk [RR]: 1.02, 95% confidence interval [CI]: 1.01 to 1.03) to 63% for gallbladder disease (RR: 1.63, 95% CI: 1.50 to 1.77). MR articles indicated that risks of developing GI diseases elevated with each 1 standard deviation increase in genetically predicted BMI, ranging from 11% for Crohn's disease to 189% for nonalcoholic fatty liver disease. Moreover, upper GI conditions were less susceptible, whereas hepatobiliary organs were more vulnerable to increased adiposity. Among the associations between obesity and the 17 GI conditions, causal relationships were inferred from only approximately half (10/17, 59%). This study reveals a substantial gap between observational and causal evidence, indicating that a combined approach is necessary to effectively inform public health policies and guide epidemiological research on obesity and GI diseases.
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Affiliation(s)
- Min Seo Kim
- Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Inhyeok Lee
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Pradeep Natarajan
- Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
- Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ron Do
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yeongkeun Kwon
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Marco Solmi
- Department of Psychiatry, University of Ottawa, Ontario, Canada
- Department of Mental Health, The Ottawa Hospital, Ontario, Canada
- Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
| | - Jong Yeob Kim
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea
| | - Hong-Hee Won
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea
- Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Sungsoo Park
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, Republic of Korea
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Graham S, Dmitrieva M, Vendramini-Costa DB, Francescone R, Trujillo MA, Cukierman E, Wood LD. From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression. Carcinogenesis 2024; 45:801-816. [PMID: 39514554 PMCID: PMC12098012 DOI: 10.1093/carcin/bgae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/04/2024] [Accepted: 10/02/2024] [Indexed: 11/16/2024] Open
Abstract
This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.
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Affiliation(s)
- Sarah Graham
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States
| | - Mariia Dmitrieva
- Cancer Signaling & Microenvironment Program, M&C Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Lewis Katz School of Medicine, Temple Health, Philadelphia, PA 19111, United States
| | - Debora Barbosa Vendramini-Costa
- Henry Ford Pancreatic Cancer Center, Henry Ford Health, Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, United States
| | - Ralph Francescone
- Henry Ford Pancreatic Cancer Center, Henry Ford Health, Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, United States
| | - Maria A Trujillo
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States
| | - Edna Cukierman
- Cancer Signaling & Microenvironment Program, M&C Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Lewis Katz School of Medicine, Temple Health, Philadelphia, PA 19111, United States
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, United States
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7
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Hawwash N, Sperrin M, Martin GP, Joshu CE, Florido R, Platz EA, Renehan AG. Waist circumference-years and cancer risk: a prospective study of the association and comparison of predictive performance with waist circumference and body mass index. Br J Cancer 2024; 131:1623-1634. [PMID: 39367274 PMCID: PMC11554801 DOI: 10.1038/s41416-024-02860-y] [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] [Received: 03/26/2024] [Revised: 09/09/2024] [Accepted: 09/18/2024] [Indexed: 10/06/2024] Open
Abstract
BACKGROUND Associations of waist circumferences (WC) and body mass index (BMI) measured once or over time, with cancer incidence were studied. WC is associated with some cancers independent of BMI. Analyses of cumulative central adiposity and cancer are lacking. We investigated associations between waist circumference-years, incorporating exposure time to WC ≥ 102 cm in men or ≥88 cm in women, and cancer, and compared this with single WC or BMI. METHODS Serial WC measurements taken over 9 years in the prospective Atherosclerosis Risk in Communities Study (ARIC) predicted yearly WC. Cox proportional hazards regression estimated hazard ratios (HRs) of cancer incidence for waist circumference-years, WC or BMI, measured in Visit 4. Harrell's C-statistic quantified metric predictive performances. RESULTS 10,172 participants were followed up from Visit 4 for cancer over a median 13.7 for men and 15.8 years for women. For obesity-related cancers, HRs per standard deviation waist circumference-years were 1.14 (95%CI:1.04,1.25) and 1.19 (95%CI:1.12,1.27), respectively. Differences in metric predictive performances were marginal. DISCUSSION This is the first study to identify positive associations between waist circumference-years and cancer. Waist circumference-years did not provide additional information on cancer risk beyond that of WC and BMI. BMI is routinely measured in clinic so it may be preferred over WC.
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Affiliation(s)
- Nadin Hawwash
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
- Cancer Research UK Manchester Cancer Research Centre, Manchester, UK.
| | - Matthew Sperrin
- Centre for Health Informatics, Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Glen P Martin
- Centre for Health Informatics, Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Corinne E Joshu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Roberta Florido
- Johns Hopkins University School of Medicine, Department of Medicine, Division of Cardiology, Baltimore, MD, USA
- Department of Medicine, Division of Cardiology, University of Utah, Salt Lake City, UT, USA
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Andrew G Renehan
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, Manchester, UK
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8
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Paranal RM, Wood LD, Klein AP, Roberts NJ. Understanding familial risk of pancreatic ductal adenocarcinoma. Fam Cancer 2024; 23:419-428. [PMID: 38609521 PMCID: PMC11660179 DOI: 10.1007/s10689-024-00383-2] [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] [Received: 01/27/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is the result of an accumulation of sequential genetic alterations. These genetic alterations can either be inherited, such as pathogenic germline variants that are associated with an increased risk of cancer, or acquired, such as somatic mutations that occur during the lifetime of an individual. Understanding the genetic basis of inherited risk of PDAC is essential to advancing patient care and outcomes through improved clinical surveillance, early detection initiatives, and targeted therapies. In this review we discuss factors associated with an increased risk of PDAC, the prevalence of genetic variants associated with an increased risk in patients with PDAC, estimates of PDAC risk in carriers of pathogenic germline variants in genes associated with an increased risk of PDAC. The role of common variants in pancreatic cancer risk will also be discussed.
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Affiliation(s)
- Raymond M Paranal
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Human Genetics Predoctoral Training Program, the McKusick-Nathans Department of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alison P Klein
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, MD, USA.
| | - Nicholas J Roberts
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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9
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Mandic M, Pulte D, Safizadeh F, Niedermaier T, Hoffmeister M, Brenner H. Overcoming underestimation of the association of excess weight with pancreatic cancer due to prediagnostic weight loss: Umbrella review of systematic reviews, meta-analyses, and pooled-analyses. Obes Rev 2024; 25:e13799. [PMID: 39054651 DOI: 10.1111/obr.13799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 06/18/2024] [Accepted: 06/27/2024] [Indexed: 07/27/2024]
Abstract
Elevated body mass index (BMI) is linked to increased pancreatic cancer (PC) risk. Cancer-associated weight loss can occur years before the malignancy is diagnosed. This might have led to underestimation of the BMI-PC association. However, it is unknown if and to what extent this issue has been considered in previous epidemiological studies. We searched two databases through February 19, 2024 for systematic reviews, meta-analyses, and pooled analyses examining the BMI-PC association. We extracted information on study design with a special focus on the article's examination of prediagnostic weight loss as a potential source of bias, as well as how included cohort studies addressed this concern. Thirteen review articles, meta-analyses, and pooled analyses were identified. Only five (four pooled analyses, one systematic review) considered prediagnostic weight loss in their analyses. Twenty-four of 32 identified cohort studies reported having excluded initial years of follow-up. However, only 13 studies reported results after such exclusions, and effect estimates generally increased with longer periods of exclusion. We conclude that the association of overweight and obesity with PC risk is likely larger than suggested by published epidemiological evidence. Future studies should pay careful attention to avoid or minimize potential bias resulting from prediagnostic weight loss.
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Affiliation(s)
- Marko Mandic
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Dianne Pulte
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Fatemeh Safizadeh
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Tobias Niedermaier
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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10
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Chan CH, Chang CC, Peng YC. The Clinical Significance of Pancreatic Steatosis in Pancreatic Cancer: A Hospital-Based Study. Diagnostics (Basel) 2024; 14:2128. [PMID: 39410531 PMCID: PMC11475449 DOI: 10.3390/diagnostics14192128] [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: 07/17/2024] [Revised: 09/16/2024] [Accepted: 09/23/2024] [Indexed: 10/20/2024] Open
Abstract
Background/Objectives: Pancreatic cancer remains one of the deadliest malignancies worldwide with a pressing need for early detection and intervention strategies. Emerging evidence has suggested a potential link between pancreas steatosis, characterized by excessive pancreatic fat accumulation, and an increased risk of pancreatic cancer development. This retrospective imaging study aims to elucidate the association between pancreatic steatosis and the subsequent development of pancreatic cancer. In the study, we aimed to determine the characteristics of pancreatic cancer with pancreatic steatosis. Methods: During the period of January 2022 to December 2022, we conducted a retrospective study, collecting 101 newly diagnosed pancreas cancer cases from the available image datasets. A comprehensive database of retrospective abdominal imaging studies, comprising computed tomography (CT) and magnetic resonance imaging (MRI), was established from a diverse patient population and subsequently analyzed. Inclusion criteria encompassed patients having available baseline imaging data, allowing for the assessment of pancreatic fat content. Pancreatic fat content was quantified using validated radiological techniques, while demographic, clinical, and histopathological data were all collected. The clinical data and patient characteristics were collected from medical records and analyzed. Results: Preliminary analysis revealed a significant correlation between elevated pancreatic fat content and an increased incidence of subsequent pancreatic cancer. Moreover, subgroup analysis based on age, gender, and comorbidities provided valuable insight into potential risk factors associated with this progression. Additionally, the study identified novel radiological markers that may serve as early indicators of pancreatic cancer development in individuals with pancreatic steatosis. Conclusions: In the imaging study, approximately 30% (30/101) of pancreatic cancer patients presented with pancreatic steatosis. Chronic pancreatitis emerged as the primary factor contributing to pancreatic steatosis in these patients. Importantly, pancreatic steatosis did not significantly impact the prognosis of pancreatic cancer. Follow-up data revealed no significant differences in survival duration between patients with or without pancreatic steatosis. Additionally, no association was found between pancreatic steatosis and hepatic steatosis.
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Affiliation(s)
- Chia-Hao Chan
- Department of Radiology, Taipei Veterans General Hospital Taitung Branch, Taitung 950410, Taiwan;
- Department of Radiology, Taichung Veterans General Hospital, Taichung 407219, Taiwan
| | - Chia-Chen Chang
- Department of Medical Imaging, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan;
| | - Yen-Chun Peng
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
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11
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Netto D, Frizziero M, Foy V, McNamara MG, Backen A, Hubner RA. Systemic Therapy for Metastatic Pancreatic Cancer-Current Landscape and Future Directions. Curr Oncol 2024; 31:5206-5223. [PMID: 39330013 PMCID: PMC11430697 DOI: 10.3390/curroncol31090385] [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: 07/03/2024] [Revised: 08/22/2024] [Accepted: 08/25/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence. A paucity of strong predictive risk factors mean screening programmes are difficult to implement. Historically, a lack of identifiable and actionable driver mutations, coupled with a relatively immunosuppressed tumour microenvironment, has led to a reliance on cytotoxic chemotherapy. The NAPOLI-3 trial has reported data supporting consideration of NALIRIFOX as a new first-line standard of care. Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.
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Affiliation(s)
- Daniel Netto
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Melissa Frizziero
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Victoria Foy
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Mairéad G. McNamara
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Alison Backen
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Richard A. Hubner
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
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12
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Cavazzani A, Angelini C, Gregori D, Cardone L. Cancer incidence (2000-2020) among individuals under 35: an emerging sex disparity in oncology. BMC Med 2024; 22:363. [PMID: 39232785 PMCID: PMC11376010 DOI: 10.1186/s12916-024-03574-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND Aggressive malignancies, such as pancreatic cancer, are increasingly impacting young, female populations. Our investigation centered on whether the observed trends in cancer incidence were unique to pancreatic cancer or indicative of a broader trend across various cancer types. To delve deeper into this phenomenon, we analyzed cancer incidence trends across different age and sex groups. Furthermore, we explored differences in cancer incidence within specific young subgroups aged 18 to 26 and 27 to 34, to better understand the emerging incidence trend among young individuals. METHODS This study collected cancer incidence data from one of the Surveillance, Epidemiology, and End Results cancer registry databases (SEER22), with 10,183,928 total cases from 2000 to 2020. Data were analyzed through Joinpoint trend analysis approach to evaluate sex- and age-specific trends in cancer incidence. Exposure rates were reported as Average Annual Percentage Changes (AAPCs). RESULTS The analysis revealed significant age and sex-specific disparities, particularly among individuals aged 18-26 and 27-34. Pancreatic cancer incidence rates increased more in females aged 18-26 (AAPC, 9.37% [95% CI, 7.36-11.41%]; p < .0001) than in males (4.43% [95% CI, 2.36-6.53%]; p < .0001). Notably, among gender, age, and other malignancies, young females had the highest AAPCs for pancreatic cancer. Additionally, the incidence of gastric cancer, myeloma, and colorectal malignancies also showed higher AAPCs in young females compared to males. CONCLUSIONS Recognizing emerging risk populations for highly lethal malignancies is crucial for early detection and effective disease management.
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Affiliation(s)
- Alessandro Cavazzani
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), c/o Campus Internazionale "A.Buzzati-Traverso", Via E. Ramarini, 32, Monterotondo Scalo Rome (RM), 00015, Italy
- Unit of Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, Rome, 00144, Italy
- Department of Biology, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Claudia Angelini
- Institute for Applied Computing, National Research Council (CNR), Naples, Italy
| | - Dario Gregori
- Unit of Biostatistics, Epidemiology and Public Health, University of Padova, Padua, Italy
| | - Luca Cardone
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), c/o Campus Internazionale "A.Buzzati-Traverso", Via E. Ramarini, 32, Monterotondo Scalo Rome (RM), 00015, Italy.
- Unit of Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, Rome, 00144, Italy.
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13
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Ead AS, Wirkus J, Matsukuma K, Mackenzie GG. A high-fat diet induces changes in mesenteric adipose tissue accelerating early-stage pancreatic carcinogenesis in mice. J Nutr Biochem 2024; 131:109690. [PMID: 38876394 DOI: 10.1016/j.jnutbio.2024.109690] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 06/01/2024] [Accepted: 06/09/2024] [Indexed: 06/16/2024]
Abstract
Increased adiposity is a significant risk factor for pancreatic cancer development. Multiple preclinical studies have documented that high-fat, high calorie diets, rich in omega-6 fatty acids (FA) accelerate pancreatic cancer development. However, the effect of a high-fat, low sucrose diet (HFD), on pancreatic carcinogenesis remains unclear. We evaluated the impact of a HFD on early-stage pancreatic carcinogenesis in the clinically relevant KrasLSL-G12D/+; Ptf1aCre/+ (KC) genetically engineered mouse model, and characterized the role of the mesenteric adipose tissue (MAT). Cohorts of male and female KC mice were randomly assigned to a control diet (CD) or a HFD, matched for FA composition (9:1 of omega-6 FA: omega-3 FA), and fed their diets for 8 weeks. After 8 weeks on a HFD, KC mice had significantly higher body weight, fat mass, and serum leptin compared to CD-fed KC mice. Furthermore, a HFD accelerated pancreatic acinar-to-ductal metaplasia (ADM) and proliferation, associated with increased activation of ERK and STAT3, and macrophage infiltration in the pancreas, compared to CD-fed KC mice. Metabolomics analysis of the MAT revealed sex differences between diet groups. In females, a HFD altered metabolites related to FA (α-linolenic acid and linoleic acid) and amino acid metabolism (alanine, aspartate, glutamate). In males, a HFD significantly affected pathways related to alanine, aspartate, glutamate, linoleic acid, and the citric acid cycle. A HFD accelerates early pancreatic ADM through multifaceted mechanisms, including effects at the tumor and surrounding MAT. The sex-dependent changes in MAT metabolites could explain some of the sex differences in HFD-induced pancreatic ADM.
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Affiliation(s)
- Aya S Ead
- Department of Nutrition, University of California, Davis, California, USA
| | - Joanna Wirkus
- Department of Nutrition, University of California, Davis, California, USA
| | - Karen Matsukuma
- Department of Pathology and Laboratory Medicine, Davis Medical Center, University of California, Sacramento, California, USA; University of California Davis Comprehensive Cancer Center, University of California, Sacramento, California, USA
| | - Gerardo G Mackenzie
- Department of Nutrition, University of California, Davis, California, USA; University of California Davis Comprehensive Cancer Center, University of California, Sacramento, California, USA.
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14
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Grigorescu RR, Husar-Sburlan IA, Gheorghe C. Pancreatic Cancer: A Review of Risk Factors. Life (Basel) 2024; 14:980. [PMID: 39202722 PMCID: PMC11355429 DOI: 10.3390/life14080980] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/28/2024] [Accepted: 08/01/2024] [Indexed: 09/03/2024] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal types of gastrointestinal cancer despite the latest medical advances. Its incidence has continuously increased in recent years in developed countries. The location of the pancreas can result in the initial symptoms of neoplasia being overlooked, which can lead to a delayed diagnosis and a subsequent reduction in the spectrum of available therapeutic options. The role of modifiable risk factors in pancreatic cancer has been extensively studied in recent years, with smoking and alcohol consumption identified as key contributors. However, the few screening programs that have been developed focus exclusively on genetic factors, without considering the potential impact of modifiable factors on disease occurrence. Thus, fully understanding and detecting the risk factors for pancreatic cancer represents an important step in the prevention and early diagnosis of this type of neoplasia. This review reports the available evidence on different risk factors and identifies the areas that could benefit the most from additional studies.
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Affiliation(s)
- Raluca Roxana Grigorescu
- Gastroenterology Department, “Sfanta Maria” Hospital, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | | | - Cristian Gheorghe
- Center for Digestive Disease and Liver Transplantation, Fundeni Clinical Institute, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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15
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Nawacki Ł, Gorczyca-Głowacka I, Zieliński P, Znamirowski P, Kozłowska-Geller M, Ciba-Stemplewska A, Kołomańska M. A 22-G or a 25-G Needle: Which One to Use in the Diagnostics of Solid Pancreatic Lesions? A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 16:2266. [PMID: 38927971 PMCID: PMC11202301 DOI: 10.3390/cancers16122266] [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: 05/07/2024] [Revised: 06/04/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
With the 12th highest incidence and a common late diagnostic at advanced stages, neoadjuvant therapies for pancreatic cancer are important, but they require a confirmed diagnosis. Being a diagnostic standard, the clarification of the clinical relevance of needle gauges is needed, as larger ones may retrieve more tissue for diagnostics, but may also increase the risk of complications. We performed a meta-analysis to compare the efficiency of the most commonly used 22-G and 25-G needles for EUS guided biopsy in solid pancreatic lesions. The MEDLINE (via PubMed), Embase, Cochrane (CENTRAL), and Scopus databases were searched with "EUS", "needle", "FNA", "pancreas", "prospective", "22G", and "25G" keywords. Mixed effects were assessed in the model, with a mean of 86% and a 95% confidence interval. Fourteen prospective studies that compared the efficiency of 22-G and 25-G biopsy needles in 508 and 524 lesions, respectively, were analyzed, along with 332 specimens biopsied using both needle sizes. The groups did not significantly differ in the outcomes. A low degree of heterogeneity was observed overall, except for specimen adequacy. Moreover, 22-G and 25-G needles have comparable safety and efficacy for focal pancreatic lesion biopsies without a high risk of complications.
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Affiliation(s)
- Łukasz Nawacki
- Collegium Medicum, The Jan Kochanowski University in Kielce, Aleja IX Wieków Kielc 19A, 25-317 Kielce, Poland (M.K.)
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16
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Jones A, Netto J, Foote T, Ruliffson B, Whittington C. Combined effects of matrix stiffness and obesity-associated signaling directs progressive phenotype in PANC-1 pancreatic cancer cells in vitro. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.11.598541. [PMID: 38915620 PMCID: PMC11195209 DOI: 10.1101/2024.06.11.598541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Obesity is a leading risk factor of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor disease prognosis and outcomes. Retrospective studies have identified this link, but interactions surrounding obesity and PDAC are still unclear. Research has shifted to contributions of fibrosis (desmoplasia) on malignancy, which involves increased deposition of collagens and other extracellular matrix (ECM) molecules and increased ECM crosslinking, all of which contribute to increased tissue stiffening. However, fibrotic stiffening is underrepresented as a model feature in current PDAC models. Fibrosis is shared between PDAC and obesity, and can be leveraged for in vitro model design, as current animal obesity models of PDAC are limited in their ability to isolate individual components of fibrosis to study cell behavior. In the current study, methacrylated type I collagen (PhotoCol®) was photo-crosslinked to pathological stiffness levels to recapitulate fibrotic ECM stiffening. PANC-1 cells were encapsulated within PhotoCol®, and the tumor-tissue constructs were prepared to represent normal (healthy) (~600 Pa) and pathological (~2000 Pa) tissues. Separately, human mesenchymal stem cells were differentiated into adipocytes representing lean (2D differentiation) and obese fat tissue (3D collagen matrix differentiation), and conditioned media was applied to PANC-1 tumor-tissue constructs. Conditioned media from obese adipocytes showed increased vimentin expression, a hallmark of invasiveness and progression, that was not seen after exposure to media from lean adipocytes or control media. Characterization of the obese adipocyte secretome suggested that some PANC-1 differences may arise from increased interleukin-8 and -10 compared to lean adipocytes. Additionally, high matrix stiffness associated induced an amoeboid morphology in PANC-1 cells that was not present at low stiffness. Amoeboid morphology is an accessory to epithelial-to-mesenchymal transition and is used to navigate complex ECM environments. This plasticity has greater implications for treatment efficacy of metastatic cancers. Overall, this work 1) highlights the importance of investigating PDAC-obesity interactions to study the effects on disease progression and persistence, 2) establishes PhotoCol® as a matrix material that can be leveraged to study amoeboid morphology and invasion in PDAC, and 3) emphasizes the importance of integrating both biophysical and biochemical interactions associated within both pathologies for in vitro PDAC models.
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Affiliation(s)
- A.E Jones
- Worcester Polytechnic Institute, Department of Biomedical Engineering
| | - J.F. Netto
- Worcester Polytechnic Institute, Department of Biomedical Engineering
| | - T.L. Foote
- Worcester Polytechnic Institute, Department of Biomedical Engineering
| | - B.N.K. Ruliffson
- Worcester Polytechnic Institute, Department of Biomedical Engineering
| | - C.F. Whittington
- Worcester Polytechnic Institute, Department of Biomedical Engineering
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17
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Zhang Y, Zhang H, Liu B, Ning K. Highly accurate diagnosis of pancreatic cancer by integrative modeling using gut microbiome and exposome data. iScience 2024; 27:109294. [PMID: 38450156 PMCID: PMC10915599 DOI: 10.1016/j.isci.2024.109294] [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: 07/06/2023] [Revised: 10/07/2023] [Accepted: 02/16/2024] [Indexed: 03/08/2024] Open
Abstract
The noninvasive detection of pancreatic ductal adenocarcinoma (PDAC) remains an immense challenge. In this study, we proposed a robust, accurate, and noninvasive classifier, namely Multi-Omics Co-training Graph Convolutional Networks (MOCO-GCN). It achieved high accuracy (0.9 ± 0.06), F1 score (0.9± 0.07), and AUROC (0.89± 0.08), surpassing contemporary approaches. The performance of model was validated on an external cohort of German PDAC patients. Additionally, we discovered that the exposome may impact PDAC development through its complex interplay with gut microbiome by mediation analysis. For example, Fusobacterium hwasookii nucleatum, known for its ability to induce inflammatory responses, may serve as a mediator for the impact of rheumatoid arthritis on PDAC. Overall, our study sheds light on how exposome and microbiome in concert could contribute to PDAC development, and enable PDAC diagnosis with high fidelity and interpretability.
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Affiliation(s)
- Yuli Zhang
- School of Mathematics, Shandong University, Jinan 250200, Shandong, China
| | - Haohong Zhang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Center of AI Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China
| | - Bingqiang Liu
- School of Mathematics, Shandong University, Jinan 250200, Shandong, China
| | - Kang Ning
- Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular-imaging, Center of AI Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China
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18
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Bogumil D, Stram D, Preston DL, Pandol SJ, Wu AH, McKean-Cowdin R, Conti DV, Setiawan VW. Excess pancreatic cancer risk due to smoking and modifying effect of quitting smoking: The Multiethnic Cohort Study. Cancer Causes Control 2024; 35:541-548. [PMID: 37924460 PMCID: PMC10838846 DOI: 10.1007/s10552-023-01811-x] [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] [Received: 04/04/2023] [Accepted: 10/02/2023] [Indexed: 11/06/2023]
Abstract
PURPOSE Risk factors for pancreatic cancer include racial/ethnic disparities and smoking. However, risk trajectories by smoking history and race/ethnicity are unknown. We examined the association of smoking with pancreatic cancer by race/ethnicity to generate age-specific incidence estimates by smoking history. METHODS We modeled pancreatic cancer incidence by race/ethnicity, age, pack-years, and years-quit using an excess relative risk model for 182,011 Multiethnic Cohort participants. We tested heterogeneity of smoking variables and pancreatic cancer by race/ethnicity and predicted incidence by smoking history. RESULTS We identified 1,831 incident pancreatic cancer cases over an average 19.3 years of follow-up. Associations of pack-years (p interaction by race/ethnicity = 0.41) and years-quit (p interaction = 0.83) with pancreatic cancer did not differ by race/ethnicity. Fifty pack-years smoked was associated with 91% increased risk (95% CI 54%, 127%) relative to never smokers in the combined sample. Every year quit corresponded to 9% decreased excess risk (95% CI 2%, 15%) from pack-years smoked. Differences in baseline pancreatic cancer risk across racial/ethnic groups (p < 0.001) translated to large differences in risk for smokers at older ages across racial/ethnic groups (65-122 cases per 100,000 at age 70). CONCLUSION Smoking pack-years were positively associated with elevated pancreatic cancer risk. Predicted risk trajectories showed a high impact of smoking cessation at < 65 years. Although we did not identify significant heterogeneity in the association of pack-years or years quit with pancreatic cancer risk, current smoker risk varied greatly by race/ethnicity in later life due to large differences in baseline risk.
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Affiliation(s)
- David Bogumil
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Room 1517C, Los Angeles, CA, 90033, USA.
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
| | - Daniel Stram
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Room 1517C, Los Angeles, CA, 90033, USA
| | | | - Stephen J Pandol
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Veterans Affairs, Los Angeles, CA, USA
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Room 1517C, Los Angeles, CA, 90033, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Roberta McKean-Cowdin
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Room 1517C, Los Angeles, CA, 90033, USA
| | - David V Conti
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Room 1517C, Los Angeles, CA, 90033, USA
- Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Veronica Wendy Setiawan
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1450 Biggy Street, Room 1517C, Los Angeles, CA, 90033, USA
- Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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19
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Kim HS, Choi YH, Lee JS, Jo IH, Ko SW, Paik KH, Choi HH, Lee HH, Lim YS, Paik CN, Lee IS, Chang JH. Characteristics of Early Pancreatic Cancer: Comparison between Stage 1A and Stage 1B Pancreatic Cancer in Multicenter Clinical Data Warehouse Study. Cancers (Basel) 2024; 16:944. [PMID: 38473306 DOI: 10.3390/cancers16050944] [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: 02/06/2024] [Revised: 02/22/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Little is known about the characteristics of early pancreatic cancer. We aimed to identify the characteristics, clues for early detection, and prognostic factors for early pancreatic cancer by analyzing a large number of patients with stage 1 pancreatic cancer. METHODS A clinical data warehouse that includes databases of all the medical records of eight academic institutions was used to select and analyze patients with pancreatic cancer that had been diagnosed from January 2010 to May 2023. RESULTS In total, 257 stage 1 pancreatic cancer patients were included. There were 134 men (52%), and the average age was 67.2 ± 9.9 years. Compared to patients with stage 1B pancreatic cancer (2-4 cm), patients with stage 1A pancreatic cancer (≤2 cm) had more tumors in the body and tail than in the head (p = 0.028), more new-onset diabetes and less old diabetes (p = 0.010), less jaundice (p = 0.020), more follow-up of IPMN (intraductal papillary mucinous neoplasm, p = 0.029), and more histories of acute pancreatitis (p = 0.013). The pathological findings showed that stage 1A pancreatic cancer involved more IPMNs (p < 0.001) and lower pancreatic intraepithelial neoplasia (p = 0.004). IPMN was present in all 13 pancreatic tumors that were smaller than 1 cm. In multivariate analysis, positive resection margin (odds ratio [OR] 1.536, p = 0.040), venous invasion (OR 1.710, p = 0.010), and perineural invasion (OR 1.968, p = 0.002) were found to be risk factors affecting disease-free survival, while old diabetes (odds ratio [OS] 1.981, p = 0.003) and perineural invasion (OR 2.270, p = 0.003) were found to be risk factors affecting overall survival. CONCLUSIONS IPMN is closely associated with early pancreatic cancer and may provide an opportunity for early detection. The presence of perineural invasion was a crucial prognostic factor for both overall and disease-free survival in patients with stage 1 pancreatic cancer.
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Affiliation(s)
- Hyo Suk Kim
- Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon 14647, Republic of Korea
| | - Young Hoon Choi
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jae Sin Lee
- Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon 21432, Republic of Korea
| | - Ik Hyun Jo
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Republic of Korea
| | - Sung Woo Ko
- Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Republic of Korea
| | - Kyu Hyun Paik
- Department of Internal Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon 34943, Republic of Korea
| | - Hyun Ho Choi
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 11765, Republic of Korea
| | - Han Hee Lee
- Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 07345, Republic of Korea
| | - Yeon Soo Lim
- Department of Radiology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon 14647, Republic of Korea
| | - Chang Nyol Paik
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Republic of Korea
| | - In Seok Lee
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jae Hyuck Chang
- Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon 14647, Republic of Korea
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20
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Wang X, Liu C, Yang Y, Huang X, Yu J. Burden of pancreatic cancer in older adults globally, regionally, and in 204 countries: 1990-2019 and projections to 2030. J Gastrointest Surg 2024; 28:121-131. [PMID: 38445933 DOI: 10.1016/j.gassur.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 10/28/2023] [Indexed: 03/07/2024]
Abstract
BACKGROUND Global aging is increasing; however, the epidemiologic characteristics of pancreatic cancer in older adults have not been systematically studied. METHODS This study used data on pancreatic cancer in older adults from the Global Burden of Disease 2019 project. Temporal trends were measured using average annual percentage change and predicted using a Bayesian age-period-cohort model. In addition, the inequality slope index and the health concentration index scores were calculated to quantify the unequal distribution of the burden of pancreatic cancer in older adults. RESULTS Between 1990 and 2019, the number of pancreatic cancer deaths in older adults, age-standardized death rate (ASDR), disability-adjusted life years (DALYs), and age-standardized DALY rate increased globally. In 2019, ASDR and age-standardized DALY rate for pancreatic cancer in older adults were the highest in Southern Latin America, whereas the burden has grown the fastest over the past 30 years in the Caribbean. The burden is predominantly distributed among those aged 65 to 74 years, with males having a higher burden than that of females. The global proportion of pancreatic cancer deaths in older adults attributed to smoking, high fasting plasma glucose, and high body mass index were 21.7%, 10.3%, and 5.8%, respectively. Both absolute and relative cross-national inequalities declined over the past 30 years but remained at medium-high levels of relative inequality. Deaths from pancreatic cancer among older adults are expected to continue to increase over the next 11 years. CONCLUSION The global burden of pancreatic cancer among older adults has continued to rise over the past 30 years, and cross-national health inequalities remain high. Therefore, targeted measures must be taken to address this inequality.
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Affiliation(s)
- Xuan Wang
- Department of Surgery, Suixi County Hospital, Anhui, China; Department of Hepatobiliary and Pancreatic Surgery, Fuyang People's Hospital, Anhui Medical University, Fuyang, China
| | - Chunlong Liu
- Department of Hepatobiliary and Pancreatic Surgery, Fuyang People's Hospital, Anhui Medical University, Fuyang, China
| | - Yong Yang
- Department of Surgery, Suixi County Hospital, Anhui, China
| | - Xiachun Huang
- Department of Surgery, Suixi County Hospital, Anhui, China.
| | - Jiangtao Yu
- Department of Hepatobiliary and Pancreatic Surgery, Fuyang People's Hospital, Anhui Medical University, Fuyang, China.
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21
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Pagkali A, Makris A, Brofidi K, Agouridis AP, Filippatos TD. Pathophysiological Mechanisms and Clinical Associations of Non-Alcoholic Fatty Pancreas Disease. Diabetes Metab Syndr Obes 2024; 17:283-294. [PMID: 38283640 PMCID: PMC10813232 DOI: 10.2147/dmso.s397643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 12/29/2023] [Indexed: 01/30/2024] Open
Abstract
Non-Alcoholic Fatty Pancreas disease (NAFPD), characterized by fat accumulation in pancreatic tissue, is an emerging clinical entity. However, the clinical associations, the underlying molecular drivers, and the pathophysiological mechanisms of NAFPD have not yet been characterized in detail. The NAFPD spectrum not only includes infiltration and accumulation of fat within and between pancreatic cells but also involves several inflammatory processes, dysregulation of physiological metabolic pathways, and hormonal defects. A deeper understanding of the underlying molecular mechanisms is key to correlate NAFPD with clinical entities including non-alcoholic fatty liver disease, metabolic syndrome, diabetes mellitus, atherosclerosis, as well as pancreatic cancer and pancreatitis. The aim of this review is to examine the pathophysiological mechanisms of NAFPD and to assess the possible causative/predictive risk factors of NAFPD-related clinical syndromes.
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Affiliation(s)
- Antonia Pagkali
- School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasios Makris
- School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Kalliopi Brofidi
- Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Aris P Agouridis
- School of Medicine, European University Cyprus, Nicosia, Cyprus
- Department of Internal Medicine, German Oncology Center, Limassol, Cyprus
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22
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Anuranjana P, Beegum F, K.P D, George KT, Viswanatha G, Nayak PG, Kanwal A, Kishore A, Shenoy RR, Nandakumar K. Mechanisms Behind the Pharmacological Application of Biochanin-A: A review. F1000Res 2023; 12:107. [PMID: 38106650 PMCID: PMC10725524 DOI: 10.12688/f1000research.126059.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/30/2023] [Indexed: 12/19/2023] Open
Abstract
This review was aimed at summarizing the cellular and molecular mechanisms behind the various pharmacological actions of biochanin-A. Many studies have been reported claiming its application in cancers, metabolic disorders, airway hyperresponsiveness, cardiac disorders, neurological disorders, etc. With regard to hormone-dependent cancers like breast, prostate, and other malignancies like pancreatic, colon, lung, osteosarcoma, glioma that has limited treatment options, biochanin-A revealed agreeable results in arresting cancer development. Biochanin-A has also shown therapeutic benefits when administered for neurological disorders, diabetes, hyperlipidaemia, and other chronic diseases/disorders. Isoflavones are considered phenomenal due to their high efficiency in modifying the physiological functions of the human body. Biochanin-A is one among the prominent isoflavones found in soy (glycine max), red clover (Trifolium pratense), and alfalfa sprouts, etc., with proven potency in modulating vital cellular mechanisms in various diseases. It has been popular for ages among menopausal women in controlling symptoms. In view of the multi-targeted functions of biochanin-A, it is essential to summarize it's mechanism of action in various disorders. The safety and efficacy of biochanin-A needs to be established in clinical trials involving human subjects. Biochanin-A might be able to modify various systems of the human body like the cardiovascular system, CNS, respiratory system, etc. It has shown a remarkable effect on hormonal cancers and other cancers. Many types of research on biochanin-A, particularly in breast, lung, colon, prostate, and pancreatic cancers, have shown a positive impact. Through modulating oxidative stress, SIRT-1 expression, PPAR gamma receptors, and other multiple mechanisms biochanin-A produces anti-diabetic action. The diverse molecular mechanistic pathways involved in the pharmacological ability of biochanin-A indicate that it is a very promising molecule and can play a major impact in modifying several physiological functions.
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Affiliation(s)
- P.V. Anuranjana
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Fathima Beegum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Divya K.P
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Krupa Thankam George
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | | | - Pawan G. Nayak
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Abhinav Kanwal
- Department of Pharmacology, All India Institute of Medical Sciences, Bathinda, Punjab, India
| | - Anoop Kishore
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Rekha R. Shenoy
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - K. Nandakumar
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
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Ruiz CF, Garcia C, Jacox JB, Lawres L, Muzumdar MD. Decoding the obesity-cancer connection: lessons from preclinical models of pancreatic adenocarcinoma. Life Sci Alliance 2023; 6:e202302228. [PMID: 37648285 PMCID: PMC10474221 DOI: 10.26508/lsa.202302228] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 09/01/2023] Open
Abstract
Obesity is a metabolic state of energy excess and a risk factor for over a dozen cancer types. Because of the rising worldwide prevalence of obesity, decoding the mechanisms by which obesity promotes tumor initiation and early progression is a societal imperative and could broadly impact human health. Here, we review results from preclinical models that link obesity to cancer, using pancreatic adenocarcinoma as a paradigmatic example. We discuss how obesity drives cancer development by reprogramming the pretumor or tumor cell and its micro- and macro-environments. Specifically, we describe evidence for (1) altered cellular metabolism, (2) hormone dysregulation, (3) inflammation, and (4) microbial dysbiosis in obesity-driven pancreatic tumorigenesis, denoting variables that confound interpretation of these studies, and highlight remaining gaps in knowledge. Recent advances in preclinical modeling and emerging unbiased analytic approaches will aid in further unraveling the complex link between obesity and cancer, informing novel strategies for prevention, interception, and therapy in pancreatic adenocarcinoma and other obesity-associated cancers.
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Affiliation(s)
- Christian F Ruiz
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
| | - Cathy Garcia
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
| | - Jeremy B Jacox
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
- Department of Medicine (Section of Medical Oncology), Yale University School of Medicine, New Haven, CT, USA
| | - Lauren Lawres
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Mandar D Muzumdar
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Biology Institute, Yale University, West Haven, CT, USA
- Department of Medicine (Section of Medical Oncology), Yale University School of Medicine, New Haven, CT, USA
- Yale Cancer Center, Yale University, New Haven, CT, USA
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24
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Babic A, Wang QL, Lee AA, Yuan C, Rifai N, Luo J, Tabung FK, Shadyab AH, Wactawski-Wende J, Saquib N, Kim J, Kraft P, Sesso HD, Buring JE, Giovannucci EL, Manson JE, Stampfer MJ, Ng K, Fuchs CS, Wolpin BM. Sex-Specific Associations between Adiponectin and Leptin Signaling and Pancreatic Cancer Survival. Cancer Epidemiol Biomarkers Prev 2023; 32:1458-1469. [PMID: 37555827 PMCID: PMC10592159 DOI: 10.1158/1055-9965.epi-23-0505] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/17/2023] [Accepted: 08/07/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Circulating adiponectin and leptin have been associated with risk of pancreatic cancer. However, the relationship between long-term exposure to these adipokines in the prediagnostic period with patient survival has not been investigated. METHODS Adipokine levels were measured in prospectively collected samples from 472 patients with pancreatic cancer. Because of sex-specific differences in adipokine levels, associations were evaluated separately for men and women. In a subset of 415 patients, we genotyped 23 SNPs in adiponectin receptor genes (ADIPOR1 and ADIPOR2) and 30 SNPs in the leptin receptor gene (LEPR). RESULTS Adiponectin levels were inversely associated with survival in women [HR, 1.71; 95% confidence interval (CI), 1.15-2.54]; comparing top with bottom quartile but not in men (HR, 0.89; 95% CI, 0.46-1.70). The SNPs rs10753929 and rs1418445 in ADIPOR1 were associated with survival in the combined population (per minor allele HR, 0.66; 95% CI, 0.51-0.84, and HR, 1.33; 95% CI, 1.12-1.58, respectively). Among SNPs in LEPR, rs12025906, rs3790431, and rs17127601 were associated with survival in the combined population [HRs, 1.54 (95% CI, 1.25-1.90), 0.72 (95% CI, 0.59-0.88), and 0.70 (95% CI, 0.56-0.89), respectively], whereas rs11585329 was associated with survival in men only (HR, 0.39; 95% CI, 0.23-0.66; Pinteraction = 0.0002). CONCLUSIONS High levels of adiponectin in the prediagnostic period were associated with shorter survival among women, but not among men with pancreatic cancer. Several polymorphisms in ADIPOR1 and LEPR are associated with patient survival. IMPACT Our findings reveal the association between adipokine signaling and pancreatic cancer survival and demonstrate the importance of examining obesity-associated pathways in relation to pancreatic cancer in a sex-specific manner.
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Affiliation(s)
- Ana Babic
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Qiao-Li Wang
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Alice A. Lee
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Nader Rifai
- Department of Laboratory Medicine, Children’s Hospital Boston, Boston, MA
| | - Juhua Luo
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, IN
| | - Fred K. Tabung
- Department of Internal Medicine, Ohio State University, Columbus, OH
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Aladdin H. Shadyab
- Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA
| | - Jean Wactawski-Wende
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, State University of New York, Buffalo, NY
| | - Nazmus Saquib
- College of Medicine, Sulaiman Al Rajhi University, Al Bukairiyah, Kingdom of Saudi Arabia
| | - Jihye Kim
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Peter Kraft
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Howard D. Sesso
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Julie E. Buring
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA
| | - Edward L. Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA
| | - JoAnn E. Manson
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA
| | - Meir J. Stampfer
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Charles S. Fuchs
- Hematology and Oncology Product Development, Genentech & Roche, South San Francisco, CA
| | - Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
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25
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Xiang X, Chen X, He Y, Wang Y, Xia W, Ye S, Wang S, Xiao Y, Li Q, Wang X, Luo W, Li J. Pancreatic cancer challenge in 52 Asian countries: age-centric insights and the role of modifiable risk factors (1990-2019). Front Oncol 2023; 13:1271370. [PMID: 37849795 PMCID: PMC10577443 DOI: 10.3389/fonc.2023.1271370] [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: 08/10/2023] [Accepted: 09/19/2023] [Indexed: 10/19/2023] Open
Abstract
Background Pancreatic cancer is renowned for its elevated incidence and mortality rates on a global scale. The disease burden of pancreatic cancer is anticipated to increase, particularly in Asia, due to its vast and rapidly aging population. Methods Data from the Global Burden of Disease 2019 were analyzed for pancreatic cancer burden across 52 countries in Asia, including the incidence, mortality, and disability-adjusted life years (DALY) for pancreatic cancer, with a focus on risk factors such as high body mass index (BMI), elevated fasting plasma glucose, and smoking. We applied the Estimated Annual Percentage Change, the Age-Period-Cohort model, and decomposition analysis to evaluate incidence trends and effects. Results From 1990 to 2019, both incidence and mortality rates of pancreatic cancer in Asia significantly increased, with an average annual standardized incidence rate change of 1.73%. Males consistently exhibited higher rates than females, with smoking as a key risk factor. Central Asia reported the highest rates, and South Asia the lowest. The incidence rose with age, peaking in those aged 70~74. The disease burden increased in all age groups, particularly in populations aged 55 and above, representing 84.41% of total cases in 2019, up from 79.01% in 1990. Pancreatic cancer ranked the fifth in incidence among six major gastrointestinal tumors but presented a significant growth rate of mortality and DALY. Conclusion With the growing, aging population in Asia, the pancreatic cancer burden is projected to escalate, bringing a significant public health challenge. Hence, comprehensive public health strategies emphasizing early detection, risk modification, and optimized treatment of pancreatic cancer are imperative.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Weiwei Luo
- *Correspondence: Weiwei Luo, ; Jingbo Li,
| | - Jingbo Li
- *Correspondence: Weiwei Luo, ; Jingbo Li,
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26
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Koltai T. Earlier Diagnosis of Pancreatic Cancer: Is It Possible? Cancers (Basel) 2023; 15:4430. [PMID: 37760400 PMCID: PMC10526520 DOI: 10.3390/cancers15184430] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/31/2023] [Accepted: 08/06/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires C1094, Argentina
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27
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Walsh RM, Ambrose J, Jack JL, Eades AE, Bye B, Ruckert MT, Olou AA, Messaggio F, Chalise P, Pei D, VanSaun MN. Adipose-Tumor Crosstalk contributes to CXCL5 Mediated Immune Evasion in PDAC. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.15.553432. [PMID: 37645755 PMCID: PMC10461999 DOI: 10.1101/2023.08.15.553432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Background CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. Cytokines responsible for stimulating these receptors include CXCL ligands, typically secreted by activated immune cells, fibroblasts, and even adipocytes. Obesity has been linked to poor patient outcome and altered anti-tumor immunity. Adipose-derived cytokines and chemokines have been implicated as potential drivers of tumor cell immune evasion, suggesting a possibility of susceptibility to targeting specifically in the context of obesity. Methods RNA-sequencing of human PDAC cell lines was used to assess differential influences on the cancer cell transcriptome after treatment with conditioned media from peri-pancreatic adipose tissue of lean and obese PDAC patients. The adipose-induced secretome of PDAC cells was then assessed by cytokine arrays and ELISAs. Lentiviral transduction and CRISPR-Cas9 was used to knock out CXCL5 from a murine PDAC cell line for orthotopic tumor studies in diet-induced obese, syngeneic mice. Flow cytometry was used to define the immune profiles of tumors. Anti-PD-1 immune checkpoint blockade therapy was administered to alleviate T cell exhaustion and invoke an immune response, while the mice were monitored at endpoint for differences in tumor size. Results The chemokine CXCL5 was secreted in response to stimulation of PDAC cells with human adipose conditioned media (hAT-CM). PDAC CXCL5 secretion was induced by either IL-1β or TNF, but neutralization of both was required to limit secretion. Ablation of CXCL5 from tumors promoted an immune phenotype susceptible to PD-1 inhibitor therapy. While application of anti-PD-1 treatment to control tumors failed to alter tumor growth, knockout CXCL5 tumors were diminished. Conclusions In summary, our findings show that known adipokines TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro. In vivo , CXCL5 depletion alone is sufficient to promote T cell infiltration into tumors in an obese setting, but requires checkpoint blockade inhibition to alleviate tumor burden. DATA AVAILABILITY STATEMENT Raw and processed RNAseq data will be further described in the GEO accession database ( awaiting approval from GEO for PRJ number ). Additional raw data is included in the supplemental material and available upon reasonable request. WHAT IS ALREADY KNOWN ON THIS TOPIC Obesity is linked to a worsened patient outcome and immunogenic tumor profile in PDAC. CXCR1/2 inhibitors have begun to be implemented in combination with immune checkpoint blockade therapies to promote T cell infiltration under the premise of targeting the myeloid rich TME. WHAT THIS STUDY ADDS Using in vitro/ex vivo cell and tissue culture-based assays with in vivo mouse models we have identified that adipose derived IL-1β and TNF can promote tumor secretion of CXCL5 which acts as a critical deterrent to CD8 T cell tumor infiltration, but loss of CXCL5 also leads to a more immune suppressive myeloid profile. HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY This study highlights a mechanism and emphasizes the efficacy of single CXCR1/2 ligand targeting that could be beneficial to overcoming tumor immune-evasion even in the obese PDAC patient population.
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28
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Partyka O, Pajewska M, Kwaśniewska D, Czerw A, Deptała A, Budzik M, Cipora E, Gąska I, Gazdowicz L, Mielnik A, Sygit K, Sygit M, Krzych-Fałta E, Schneider-Matyka D, Grochans S, Cybulska AM, Drobnik J, Bandurska E, Ciećko W, Ratajczak P, Kamecka K, Marczak M, Kozłowski R. Overview of Pancreatic Cancer Epidemiology in Europe and Recommendations for Screening in High-Risk Populations. Cancers (Basel) 2023; 15:3634. [PMID: 37509296 PMCID: PMC10377815 DOI: 10.3390/cancers15143634] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/11/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Pancreatic cancer is the seventh most common cause of death in the group of oncological diseases. Due to the asymptomatic course, early diagnosis is difficult. Currently, early detection methods are only used in high-risk groups. A literature review based on the available results of observational studies on patients with pancreatic cancer and people from high-risk groups was used to summarize the knowledge on risk factors. The GLOBOCAN 2020 data were used to assess the epidemiological situation in Europe. A summary of screening recommendations was prepared based on the available documents from medical organizations and associations. Pancreatic cancer risk factors are divided into two main groups: non-modifiable factors, e.g., hereditary factors and age, which increase the risk of developing this disease, and modifiable factors-BMI, smoking, and alcohol consumption. Hereditary factors account for 10% of pancreatic cancer cases. The highly specialized methods of early detection, (MRI, CT, or EUS) are used for screening high-risk populations. Of all the imaging methods, EUS is considered the most sensitive for pancreatic cancer and allows an accurate assessment of the size of even small lesions (<30 mm) and the extent of tumour infiltration into blood vessels. The available studies vary on the level of sensitivity and specificity of these methods for the diagnosis of pancreatic cancer. EUS, MRI, and CT are also expensive procedures and in some patients can be invasive, which is one of the arguments against the introduction of population screening programs based on imaging methods. Therefore, it is important to look for viable solutions that would improve early detection. This is important from the point of view of healthcare systems in Europe, where almost 29% of all global pancreatic cancer cases are reported.
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Affiliation(s)
- Olga Partyka
- Department of Health Economics and Medical Law, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Monika Pajewska
- Department of Health Economics and Medical Law, Medical University of Warsaw, 01-445 Warsaw, Poland
- Department of Economic and System Analyses, National Institute of Public Health NIH-National Research Institute, 00-791 Warsaw, Poland
| | - Daria Kwaśniewska
- Department of Oncology, The National Institute of Medicine of the Ministry of Interior and Administration, 02-507 Warsaw, Poland
| | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 01-445 Warsaw, Poland
- Department of Economic and System Analyses, National Institute of Public Health NIH-National Research Institute, 00-791 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Michał Budzik
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Elżbieta Cipora
- Medical Institute, Jan Grodek State University in Sanok, 38-500 Sanok, Poland
| | - Izabela Gąska
- Medical Institute, Jan Grodek State University in Sanok, 38-500 Sanok, Poland
| | - Lucyna Gazdowicz
- Medical Institute, Jan Grodek State University in Sanok, 38-500 Sanok, Poland
| | - Aneta Mielnik
- Medical Institute, Jan Grodek State University in Sanok, 38-500 Sanok, Poland
| | - Katarzyna Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Marian Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Edyta Krzych-Fałta
- Department of Basic of Nursing, Faculty of Health Sciences, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Daria Schneider-Matyka
- Department of Nursing, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Szymon Grochans
- Department of Specialised Nursing, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Anna M Cybulska
- Department of Nursing, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Jarosław Drobnik
- Department of Family Medicine, Faculty of Medicine, Wrocław Medical University, 51-141 Wrocław, Poland
| | - Ewa Bandurska
- Center for Competence Development, Integrated Care and e-Health, Medical University of Gdansk, 80-204 Gdansk, Poland
| | - Weronika Ciećko
- Center for Competence Development, Integrated Care and e-Health, Medical University of Gdansk, 80-204 Gdansk, Poland
| | - Piotr Ratajczak
- Department of Pharmacoeconomics and Social Pharmacy, Poznan University of Medical Sciences, 60-806 Poznań, Poland
| | - Karolina Kamecka
- Department of Management and Logistics in Healthcare, Medical University of Lodz, 90-131 Lodz, Poland
| | - Michał Marczak
- Collegium Management, WSB Merito University in Warsaw, 03-204 Warszawa, Poland
| | - Remigiusz Kozłowski
- Department of Management and Logistics in Healthcare, Medical University of Lodz, 90-131 Lodz, Poland
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Li J, Qian L, Shi Y, Shen B, Peng C. Short-term outcomes between robot-assisted and open pancreaticoduodenectomy in patients with high body mass index: A propensity score matched study. Cancer Med 2023; 12:15141-15148. [PMID: 37255405 PMCID: PMC10417296 DOI: 10.1002/cam4.6186] [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] [Received: 01/18/2023] [Revised: 04/27/2023] [Accepted: 05/21/2023] [Indexed: 06/01/2023] Open
Abstract
BACKGROUND High body mass index was considered as a risk factor for minimally invasive surgery. The short-term outcomes of robot-assisted pancreaticoduodenectomy (RPD) remain controversial. This study aims to investigate the feasibility and advantage of RPD in patients with high body mass index compared to open pancreaticoduodenectomy (OPD). METHODS Clinical data of 304 patients who underwent pancreaticoduodenectomy from January 2016 to December 2019 in Ruijin Hospital, Shanghai Jiao Tong University School of Medicine was collected. Patients with BMI >25 kg/m2 were included and divided into RPD and OPD group. After PSM at a 1:1 ratio, 75 patients of OPD and 75 patients of RPD were recorded and analyzed. RESULTS The RPD group showed advantages in the estimated blood loss (EBL) (323.3 mL vs. 480.7 mL, p = 0.010), the postoperative abdominal infection rate (24% vs. 44%, p = 0.010), the incidence of Clavien-Dindo III-V complications (14.7% vs. 28.0%, p = 0.042) over OPD group. CONCLUSION RPD shows advantages in less EBL, lower incidence rate of Clavien-Dindo III-V complications over OPD in overweight and obese patients. RPD was confirmed as a safe and feasible surgical approach for overweight or obsess patients.
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Affiliation(s)
- Jingfeng Li
- Department of General SurgeryPancreatic Disease CenterRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Research Institute of Pancreatic DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
- State Key Laboratory of Oncogenes and Related Genes (Shanghai)ShanghaiChina
- Institute of Translational MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Lihan Qian
- Department of General SurgeryPancreatic Disease CenterRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Research Institute of Pancreatic DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
- State Key Laboratory of Oncogenes and Related Genes (Shanghai)ShanghaiChina
- Institute of Translational MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Yusheng Shi
- Department of General SurgeryPancreatic Disease CenterRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Research Institute of Pancreatic DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
- State Key Laboratory of Oncogenes and Related Genes (Shanghai)ShanghaiChina
- Institute of Translational MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Baiyong Shen
- Department of General SurgeryPancreatic Disease CenterRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Research Institute of Pancreatic DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
- State Key Laboratory of Oncogenes and Related Genes (Shanghai)ShanghaiChina
- Institute of Translational MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Chenghong Peng
- Department of General SurgeryPancreatic Disease CenterRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Research Institute of Pancreatic DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
- State Key Laboratory of Oncogenes and Related Genes (Shanghai)ShanghaiChina
- Institute of Translational MedicineShanghai Jiao Tong UniversityShanghaiChina
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Kan C, Liu N, Zhang K, Wu D, Liang Y, Cai W, Jing Q, Han F, Xing S, Sun X. Global, Regional, and National Burden of Pancreatic Cancer, 1990-2019: Results from the Global Burden of Disease Study 2019. Ann Glob Health 2023; 89:33. [PMID: 37252335 PMCID: PMC10215993 DOI: 10.5334/aogh.4019] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 04/28/2023] [Indexed: 05/31/2023] Open
Abstract
AIMS Pancreatic cancer (PC) is a malignant tumor with a strong invasive nature and low survival rate. We aimed to estimate the PC burden at the global, regional, and national levels in 204 countries from 1990 to 2019. METHODS Detailed data, including the incidence, death, and disability-adjusted life years (DALYs), were analyzed from the Global Burden of Diseases Study 2019. RESULTS Globally, there were 530,297 (486,175-573,635) incident cases and 531,107 (491,948-566,537) deaths from PC in 2019. The age-standardized incidence rate (ASIR) was 6.6 (6-7.1), and the age-standardized mortality rate (ASMR) was 6.6 (6.1-7.1) per 100,000 person-years. PC caused 11,549,016 (10,777,405-12,338,912) DALYs, with an age-standardized rate of 139.6 (130.2-149.1) per 100,000 person-years. There were increases in estimated annual percentage changes (EAPCs) of ASIR (0.83; 0.78-0.87), ASMR (0.77; 0.73-0.81), and age-standardized DALYs rate (ASDR) (0.67; 0.63-0.71). The global number of incident cases increased by 168.7%, from 197,348 (188,604-203,971) to 530,297 (486,175-573,635); the number of deaths increased by 168.2% from 198,051 (189,329-204,763) to 531,107 (491,948-566,537); and total DALYs increased by 148.5% from 4,647,207 (4,465,440-4,812,129) to 11,549,016 (10,777,405-12,338,912). East Asia and China recorded the highest number of incident cases, deaths, and DALYs. The proportion of deaths was attributable to smoking (21.4%), elevated fasting glucose (9.1%), and high BMI (6%). CONCLUSIONS Our study updated the epidemiological trends and risk factors for PC. PC remains a major hazard to the sustainability of health systems worldwide, with an increasing incidence rate and mortality from 1990 to 2019. More targeted strategies are required to prevent and treat PC.
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Affiliation(s)
- Chengxia Kan
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Na Liu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Kexin Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Di Wu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yunzi Liang
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Weiqin Cai
- School of Management, Weifang Medical University, Weifang, China
| | - Qi Jing
- School of Management, Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Shunjie Xing
- Department of ophthalmology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
- Department of Endocrinology and Metabolism, Affiliated Hospital of Weifang Medical University, China
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31
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Abboud Y, Samaan JS, Oh J, Jiang Y, Randhawa N, Lew D, Ghaith J, Pala P, Leyson C, Watson R, Liu Q, Park K, Paski S, Osipov A, Larson BK, Hendifar A, Atkins K, Nissen NN, Li D, Pandol SJ, Lo SK, Gaddam S. Increasing Pancreatic Cancer Incidence in Young Women in the United States: A Population-Based Time-Trend Analysis, 2001-2018. Gastroenterology 2023; 164:978-989.e6. [PMID: 36775072 PMCID: PMC11364483 DOI: 10.1053/j.gastro.2023.01.022] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 12/14/2022] [Accepted: 01/09/2023] [Indexed: 02/14/2023]
Abstract
BACKGROUND & AIMS Previous studies have shown an increasing incidence of pancreatic cancer (PC), especially in younger women; however, this has not been externally validated. In addition, there are limited data about contributing factors to this trend. We report age and sex-specific time-trend analysis of PC age-adjusted incidence rates (aIRs) using the National Program of Cancer Registries database without Surveillance Epidemiology and End Results data. METHODS PC aIR, mortality rates, annual percentage change, and average annual percentage change (AAPC) were calculated and assessed for parallelism and identicalness. Age-specific analyses were conducted in older (≥55 years) and younger (<55 years) adults. PC incidence based on demographics, tumor characteristics, and mortality were evaluated in younger adults. RESULTS A total of 454,611 patients were diagnosed with PC between 2001 and 2018 with significantly increasing aIR in women (AAPC = 1.27%) and men (AAPC = 1.14%) without a difference (P = .37). Similar results were seen in older adults. However, in younger adults (53,051 cases; 42.9% women), women experienced a greater increase in aIR than men (AAPCs = 2.36%, P < .001 vs 0.62%, P = 0.62) with nonparallel trends (P < .001) and AAPC difference of 1.74% (P < .001). This AAPC difference appears to be due to rising aIR in Blacks (2.23%; P < .001), adenocarcinoma histopathologic subtype (0.89%; P = .003), and location in the head-of-pancreas (1.64%; P < .001). PC mortality was found to be unchanged in women but decreasing in counterpart men (AAPC difference = 0.54%; P = .001). CONCLUSION Using nationwide data, covering ≈64.5% of the U.S. population, we externally validate a rapidly increasing aIR of PC in younger women. There was a big separation of the incidence trend between women and men aged 15-34 years between 2001 and 2018 (>200% difference), and it did not show slowing down.
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Affiliation(s)
- Yazan Abboud
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jamil S Samaan
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Janice Oh
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Yi Jiang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Navkiran Randhawa
- Department of Internal Medicine, Franciscan Health, Olympia Fields, Illinois
| | - Daniel Lew
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jenan Ghaith
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Pranav Pala
- Kamineni Academy of Medical Sciences and Research Centre, Hyderabad, India
| | - ChristineAnn Leyson
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Rabindra Watson
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Quin Liu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Kenneth Park
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Shirley Paski
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Arsen Osipov
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Brent K Larson
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Andrew Hendifar
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Katelyn Atkins
- Cedars-Sinai Medical Center, Department of Radiation Oncology, Los Angeles, California
| | - Nicholas N Nissen
- Department of Pancreatic and Biliary Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Debiao Li
- Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephen J Pandol
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Simon K Lo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Srinivas Gaddam
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California.
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Marin AM, Sanchuki HBS, Namur GN, Uno M, Zanette DL, Aoki MN. Circulating Cell-Free Nucleic Acids as Biomarkers for Diagnosis and Prognosis of Pancreatic Cancer. Biomedicines 2023; 11:biomedicines11041069. [PMID: 37189687 DOI: 10.3390/biomedicines11041069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/15/2023] [Accepted: 03/24/2023] [Indexed: 04/05/2023] Open
Abstract
A lack of reliable early diagnostic tools represents a major challenge in the management of pancreatic cancer (PCa), as the disease is often only identified after it reaches an advanced stage. This highlights the urgent need to identify biomarkers that can be used for the early detection, staging, treatment monitoring, and prognosis of PCa. A novel approach called liquid biopsy has emerged in recent years, which is a less- or non-invasive procedure since it focuses on plasmatic biomarkers such as DNA and RNA. In the blood of patients with cancer, circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) have been identified such as DNA, mRNA, and non-coding RNA (miRNA and lncRNA). The presence of these molecules encouraged researchers to investigate their potential as biomarkers. In this article, we focused on circulating cfNAs as plasmatic biomarkers of PCa and analyzed their advantages compared to traditional biopsy methods.
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Affiliation(s)
- Anelis Maria Marin
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Prof Algacyr Munhoz Mader 3775 Street, Curitiba 81350-010, Brazil
| | - Heloisa Bruna Soligo Sanchuki
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Prof Algacyr Munhoz Mader 3775 Street, Curitiba 81350-010, Brazil
| | - Guilherme Naccache Namur
- Center for Translational Research in Oncology (LIM24), Departamento de Radiologia e Oncologia, Instituto do Câncer do Estado de São Paulo (ICESP), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo 01246-000, Brazil
| | - Miyuki Uno
- Center for Translational Research in Oncology (LIM24), Departamento de Radiologia e Oncologia, Instituto do Câncer do Estado de São Paulo (ICESP), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo 01246-000, Brazil
| | - Dalila Luciola Zanette
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Prof Algacyr Munhoz Mader 3775 Street, Curitiba 81350-010, Brazil
| | - Mateus Nóbrega Aoki
- Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Prof Algacyr Munhoz Mader 3775 Street, Curitiba 81350-010, Brazil
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Mastracci TL, Apte M, Amundadottir LT, Alvarsson A, Artandi S, Bellin MD, Bernal-Mizrachi E, Caicedo A, Campbell-Thompson M, Cruz-Monserrate Z, El Ouaamari A, Gaulton KJ, Geisz A, Goodarzi MO, Hara M, Hull-Meichle RL, Kleger A, Klein AP, Kopp JL, Kulkarni RN, Muzumdar MD, Naren AP, Oakes SA, Olesen SS, Phelps EA, Powers AC, Stabler CL, Tirkes T, Whitcomb DC, Yadav D, Yong J, Zaghloul NA, Pandol SJ, Sander M. Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases: Workshop Proceedings. Diabetes 2023; 72:433-448. [PMID: 36940317 PMCID: PMC10033248 DOI: 10.2337/db22-0942] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/29/2022] [Indexed: 03/22/2023]
Abstract
The Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report provides a summary of the proceedings from the workshop. The goals of the workshop were to forge connections and identify gaps in knowledge that could guide future research directions. Presentations were segregated into six major theme areas, including 1) pancreas anatomy and physiology, 2) diabetes in the setting of exocrine disease, 3) metabolic influences on the exocrine pancreas, 4) genetic drivers of pancreatic diseases, 5) tools for integrated pancreatic analysis, and 6) implications of exocrine-endocrine cross talk. For each theme, multiple presentations were followed by panel discussions on specific topics relevant to each area of research; these are summarized here. Significantly, the discussions resulted in the identification of research gaps and opportunities for the field to address. In general, it was concluded that as a pancreas research community, we must more thoughtfully integrate our current knowledge of normal physiology as well as the disease mechanisms that underlie endocrine and exocrine disorders so that there is a better understanding of the interplay between these compartments.
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Affiliation(s)
- Teresa L. Mastracci
- Department of Biology, Indiana University–Purdue University Indianapolis, Indianapolis, IN
| | - Minoti Apte
- Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
| | | | - Alexandra Alvarsson
- Diabetes, Obesity, and Metabolism Institute, Mount Sinai Hospital, New York, NY
| | - Steven Artandi
- Department of Internal Medicine, Stanford University, Stanford, CA
| | - Melena D. Bellin
- Departments of Pediatrics and Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - Ernesto Bernal-Mizrachi
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro Caicedo
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Martha Campbell-Thompson
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL
| | - Zobeida Cruz-Monserrate
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
| | | | - Kyle J. Gaulton
- Department of Pediatrics, University of California San Diego, La Jolla, CA
| | - Andrea Geisz
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA
| | - Mark O. Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Manami Hara
- Department of Medicine, The University of Chicago, Chicago, IL
| | - Rebecca L. Hull-Meichle
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA
| | - Alexander Kleger
- Institute of Molecular Oncology and Stem Cell Biology, Ulm University, Ulm, Germany
| | - Alison P. Klein
- Department of Pathology and Medicine, Johns Hopkins School of Medicine, Baltimore MD
| | - Janel L. Kopp
- Department of Cellular & Physiological Sciences, The University of British Columbia, Vancouver, Canada
| | | | - Mandar D. Muzumdar
- Departments of Genetics and Internal Medicine (Oncology), Yale University School of Medicine, New Haven, CT
| | | | - Scott A. Oakes
- Department of Pathology, The University of Chicago, Chicago, IL
| | - Søren S. Olesen
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Edward A. Phelps
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
| | - Alvin C. Powers
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, TN
| | - Cherie L. Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL
| | - Temel Tirkes
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN
| | | | - Dhiraj Yadav
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Jing Yong
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
| | - Norann A. Zaghloul
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Stephen J. Pandol
- Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Maike Sander
- Department of Pediatrics and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA
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Saeed U, Myklebust TÅ, Robsahm TE, Møller B, Mala T, Skålhegg BS, Yaqub S. Body mass index and pancreatic adenocarcinoma: A nationwide registry-based cohort study. Scand J Surg 2023; 112:11-21. [PMID: 36173093 DOI: 10.1177/14574969221127530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND OBJECTIVE An association between body mass index (BMI) and pancreatic cancer is suggested in observational studies. However, further studies are required to substantiate available evidence. The aim of this study was to explore the association between BMI and pancreatic ductal adenocarcinoma (PDAC) risk, treatment, and mortality. METHODS A registry-based cohort study was performed by combining data from four registries in Norway. Baseline data were collected between 1963 and 1975 with follow-up data collected until 2018. Kaplan-Meier curves and multivariable Cox regressions were estimated. Chi-square tests were used to analyze differences between groups. RESULTS The study cohort consisted of 1,723,692 individuals. A total of 8973 PDAC cases were identified during 55,744,749 person-years of follow-up. A 5 kg/m2 increase in BMI was associated with an increased risk of PDAC if high BMI at young age (16-29 years) (hazard ratio (HR): 1.21, 95% confidence interval (CI): 1.13-1.31), both for men (HR: 1.30, 95% CI: 1.15-1.46) and women (HR: 1.16, 95% CI: 1.05-1.28). In men, there was a 52% increase in risk of early-onset PDAC (<age 50) (HR: 1.52, 95% CI: 1.13-2.03) with 5 kg/m2 increase in BMI. A total of 2645 individuals were diagnosed with stage 1-3 disease, of whom 1131 underwent curative surgery. In all, 49% of normal weight, 38% overweight, and 30% obese individuals with stage 1-3 PDAC underwent surgery with curative intent (p < 0.001). Cancer survival was lower in overweight and obese individuals for both sexes. Analysis adjusted for sex, age, and period of diagnosis confirmed increased risk of cancer death in obese individuals. CONCLUSION This study suggests that increased BMI in young adults may increase the risk of PDAC, and higher BMI in men is associated with an increased risk of early onset PDAC (<age 50). Overweight and obese individuals were less likely to undergo curative surgery and obese individuals had a higher risk of cancer-related death.
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Affiliation(s)
- Usman Saeed
- Department of Gastrointestinal Surgery ,Oslo University Hospital, PO Box 4950 Nydalen N-0424 Oslo Norway
| | - Tor Å Myklebust
- Department of Registration, Cancer Registry of Norway, Oslo, Norway Department of Research and Innovation, Møre and Romsdal Hospital Trust, Ålesund, Norway
| | - Trude E Robsahm
- Department of Research, Cancer Registry of Norway, Oslo, Norway
| | - Bjørn Møller
- Department of Registration, Cancer Registry of Norway, Oslo, Norway
| | - Tom Mala
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway
| | - Bjørn S Skålhegg
- Division for Molecular Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Sheraz Yaqub
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, NorwayInstitute of Clinical Medicine, University of Oslo, Norway
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35
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Mazer BL, Lee JW, Roberts NJ, Chu LC, Lennon AM, Klein AP, Eshleman JR, Fishman EK, Canto MI, Goggins MG, Hruban RH. Screening for pancreatic cancer has the potential to save lives, but is it practical? Expert Rev Gastroenterol Hepatol 2023; 17:555-574. [PMID: 37212770 PMCID: PMC10424088 DOI: 10.1080/17474124.2023.2217354] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/21/2023] [Accepted: 05/19/2023] [Indexed: 05/23/2023]
Abstract
INTRODUCTION Most patients with pancreatic cancer present with advanced stage, incurable disease. However, patients with high-grade precancerous lesions and many patients with low-stage disease can be cured with surgery, suggesting that early detection has the potential to improve survival. While serum CA19.9 has been a long-standing biomarker used for pancreatic cancer disease monitoring, its low sensitivity and poor specificity have driven investigators to hunt for better diagnostic markers. AREAS COVERED This review will cover recent advances in genetics, proteomics, imaging, and artificial intelligence, which offer opportunities for the early detection of curable pancreatic neoplasms. EXPERT OPINION From exosomes, to circulating tumor DNA, to subtle changes on imaging, we know much more now about the biology and clinical manifestations of early pancreatic neoplasia than we did just five years ago. The overriding challenge, however, remains the development of a practical approach to screen for a relatively rare, but deadly, disease that is often treated with complex surgery. It is our hope that future advances will bring us closer to an effective and financially sound approach for the early detection of pancreatic cancer and its precursors.
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Affiliation(s)
- Benjamin L. Mazer
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jae W. Lee
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nicholas J. Roberts
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Linda C. Chu
- Department of Radiology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Anne Marie Lennon
- Department of Medicine, Division of Gastroenterology and Hepatology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alison P. Klein
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - James R. Eshleman
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elliot K. Fishman
- Department of Radiology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Marcia Irene Canto
- Department of Medicine, Division of Gastroenterology and Hepatology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael G. Goggins
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ralph H. Hruban
- The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Ruze R, Chen Y, Xu R, Song J, Yin X, Wang C, Xu Q. Obesity, diabetes mellitus, and pancreatic carcinogenesis: Correlations, prevention, and diagnostic implications. Biochim Biophys Acta Rev Cancer 2023; 1878:188844. [PMID: 36464199 DOI: 10.1016/j.bbcan.2022.188844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/13/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022]
Abstract
The prevalence of obesity, diabetes mellitus (DM), and pancreatic cancer (PC) has been consistently increasing in the last two decades worldwide. Sharing various influential risk factors in genetics and environmental inducers in pathogenesis, the close correlations of these three diseases have been demonstrated in plenty of clinical studies using multiple parameters among different populations. On the contrary, most measures aimed to manage and treat obesity and DM effectively reduce the risk and prevent PC occurrence, yet certain drugs can inversely promote pancreatic carcinogenesis instead. Most importantly, an elevation of blood glucose with or without a reduction in body weight, along with other potential tools, may provide valuable clues for detecting PC at an early stage in patients with obesity and DM, favoring a timely intervention and prolonging survival. Herein, the epidemiological and etiological correlations among these three diseases and the supporting clinical evidence of their connections are first summarized to favor a better and more thorough understanding of obesity- and DM-related pancreatic carcinogenesis. After comparing the distinct impacts of different weight-lowering and anti-diabetic treatments on the risk of PC, the possible diagnostic implications of hyperglycemia and weight loss in PC screening are also addressed in detail.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China.
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China.
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Dong M, Cao L, Cui R, Xie Y. The connection between innervation and metabolic rearrangements in pancreatic cancer through serine. Front Oncol 2022; 12:992927. [PMID: 36582785 PMCID: PMC9793709 DOI: 10.3389/fonc.2022.992927] [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: 07/13/2022] [Accepted: 10/31/2022] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is a kind of aggressive tumor famous for its lethality and intractability, and pancreatic ductal adenocarcinoma is the most common type. Patients with pancreatic cancer often suffer a rapid loss of weight and abdominal neuropathic pain in their early stages and then go through cachexia in the advanced stage. These features of patients are considered to be related to metabolic reprogramming of pancreatic cancer and abundant nerve innervation responsible for the pain. With increasing literature certifying the relationship between nerves and pancreatic ductal adenocarcinoma (PDAC), more evidence point out that innervation's role is not limited to neuropathic pain but explore its anti/pro-tumor functions in PDAC, especially the neural-metabolic crosstalks. This review aims to unite pancreatic cancer's innervation and metabolic rearrangements with terminated published articles. Hopefully, this article could explore the pathogenesis of PDAC and further promote promising detecting or therapeutic measurements for PDAC according to the lavish innervation in PDAC.
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Affiliation(s)
- Mengmeng Dong
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, China
| | - Lidong Cao
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Second Hospital of Jilin University, Changchun, China,Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Peoples Hospital, Hangzhou, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, China,*Correspondence: Ranji Cui, ; Yingjun Xie,
| | - Yingjun Xie
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, China,Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, Second Hospital of Jilin University, Changchun, China,*Correspondence: Ranji Cui, ; Yingjun Xie,
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Li J, Li Y, Chen C, Guo J, Qiao M, Lyu J. Recent estimates and predictions of 5-year survival rate in patients with pancreatic cancer: A model-based period analysis. Front Med (Lausanne) 2022; 9:1049136. [PMID: 36569146 PMCID: PMC9773388 DOI: 10.3389/fmed.2022.1049136] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/15/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The 5-year survival rate for pancreatic cancer (PC) is incredibly low, resulting in this often being a fatal disease. Timely and accurate assessment of the survival rate and prognosis of patients with PC is of great significance for the development of new programs for prevention, monitoring, and treatment. METHODS Period analysis and further stratified analysis were used to determine the 5-year relative survival rate (RSR) of patients with PC from 2002 to 2016 using the Surveillance, Epidemiology, and End Results (SEER) project database of the National Cancer Institute. Based on this, a generalized linear model was created to predict the survival rate of patients from 2017 to 2021. RESULT During 2002-2016, the 5-year RSR of patients with PC increased from 7.9 to 23.7%. The generalized linear model predicted that the survival rate had increased to 33.9% during 2017-2021, and hence, it was still unacceptably low. The survival rate of patients aged ≥75 years at diagnosis was the lowest among all age groups and was predicted to be only 21.4% during 2017-2021. Notably, the survival rate of patients with differentiation grade III at diagnosis remains particularly low at 7.6%. CONCLUSION The survival rates of patients with PC, although slightly improved, remain extremely low. Timely assessment of the trend of survival rate changes in patients with PC further improves the prognosis of tumor patients and provides data support for relevant medical works to formulate effective tumor prevention and control policies.
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Affiliation(s)
- Jing Li
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Yunmei Li
- School of Basic Medicine and Public Health, Jinan University, Guangzhou, Guangdong, China
| | - Chong Chen
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Jiayu Guo
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Mengmeng Qiao
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Jun Lyu
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization, Guangzhou, Guangdong, China
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Nishikawa M, Yamamoto J, Einama T, Hoshikawa M, Iwasaki T, Nakazawa A, Takihara Y, Tsunenari T, Kishi Y. Preoperative Rapid Weight Loss as a Prognostic Predictor After Surgical Resection for Pancreatic Cancer. Pancreas 2022; 51:1388-1397. [PMID: 37099784 DOI: 10.1097/mpa.0000000000002186] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
OBJECTIVE The aim of the study is to evaluate the influence of cachexia at the time of diagnosis of pancreatic ductal adenocarcinoma (PDAC) on prognosis in patients undergoing surgical resection. METHODS Patients with data on preoperative body weight (BW) change followed by surgical resection during 2008-2017 were selected. Large BW loss was defined as weight loss >5% or >2% in individuals with body mass index less than 20 kg/m2 within 1 year preoperatively. Influence of large BW loss, ΔBW defined as preoperative BW change (%) per month, prognostic nutrition index, and indices of sarcopenia. RESULTS We evaluated 165 patients with PDAC. Preoperatively, 78 patients were categorized as having large BW loss. ΔBW was ≤ -1.34% per month (rapid) and > -1.34% per month (slow) in 95 and 70 patients, respectively. The median postoperative overall survival of rapid and slow ΔBW groups was 1.4 and 4.4 years, respectively (P < 0.001). In multivariate analyses rapid ΔBW (hazard ratio [HR], 3.88); intraoperative blood loss ≥430 mL (HR, 1.89); tumor size ≥2.9 cm (HR, 1.74); and R1/2 resection (HR, 1.77) were independent predictors of worse survival. CONCLUSIONS Preoperative rapid BW loss ≥1.34% per month was an independent predictor of worse survival of patients with PDAC.
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Affiliation(s)
| | - Junji Yamamoto
- Department of Gastrointestinal Surgery, Ibaraki Prefectural Central Hospital, Kasama City, Japan
| | - Takahiro Einama
- From the Department of Surgery, National Defense Medical College Hospital, Tokorozawa
| | - Mayumi Hoshikawa
- Department of Gastrointestinal Surgery, Ibaraki Prefectural Central Hospital, Kasama City, Japan
| | - Toshimitsu Iwasaki
- From the Department of Surgery, National Defense Medical College Hospital, Tokorozawa
| | - Akiko Nakazawa
- From the Department of Surgery, National Defense Medical College Hospital, Tokorozawa
| | - Yasuhiro Takihara
- From the Department of Surgery, National Defense Medical College Hospital, Tokorozawa
| | - Takazumi Tsunenari
- From the Department of Surgery, National Defense Medical College Hospital, Tokorozawa
| | - Yoji Kishi
- From the Department of Surgery, National Defense Medical College Hospital, Tokorozawa
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Hoyt M, Song Y, Gao S, O'Palka J, Zhang J. Prediagnostic BMI trajectories in relation to pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Obesity (Silver Spring) 2022; 30:2275-2285. [PMID: 36156459 PMCID: PMC9826088 DOI: 10.1002/oby.23550] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/26/2022] [Accepted: 06/28/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE It remains elusive whether prediagnostic BMI trajectory is associated with pancreatic cancer. METHODS This study investigated this question among 145,489 participants who gave rise to 696 incident cases of pancreatic cancer over a median follow-up of 12 years in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. At baseline, participants were asked to recall their weight at ages 20, 50, and 55 to 74 years (at enrollment), as well as their height. RESULTS At age 50 years, people with obesity had a significantly increased risk of pancreatic cancer compared with those with a normal weight after adjustment for confounders (hazard ratio [95% CI]: 1.27 [1.01-1.60]). Individuals who had overweight at age 20 years experienced a marginally significant elevated risk of pancreatic cancer (hazard ratio [95% CI]: 1.22 [0.99-1.50]). Compared with individuals who maintained a steady normal weight during follow-up, no significantly altered risk of pancreatic cancer was observed for those whose weight status changed from normal weight to overweight, from normal weight to obesity, and from overweight to obesity. CONCLUSIONS The present study revealed that prediagnostic adulthood BMI trajectory was not associated with pancreatic cancer risk, but overweight at young adulthood and obesity at middle adulthood may confer an elevated risk of this malignancy.
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Affiliation(s)
- Margaret Hoyt
- Department of EpidemiologyRichard M. Fairbanks School of Public Health, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Yiqing Song
- Department of EpidemiologyRichard M. Fairbanks School of Public Health, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Sujuan Gao
- Department of Biostatistics and Health Data ScienceRichard M. Fairbanks School of Public Health and School of Medicine, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Jacquelynn O'Palka
- Department of Nutrition and DieteticsSchool of Health and Human Sciences, Indiana University–Purdue UniversityIndianapolisIndianaUSA
| | - Jianjun Zhang
- Department of EpidemiologyRichard M. Fairbanks School of Public Health, Indiana University–Purdue UniversityIndianapolisIndianaUSA
- Melvin and Bren Simon Comprehensive Cancer CenterIndiana University–Purdue UniversityIndianapolisIndianaUSA
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Arjani S, Saint-Maurice PF, Julián-Serrano S, Eibl G, Stolzenberg-Solomon R. Body Mass Index Trajectories Across the Adult Life Course and Pancreatic Cancer Risk. JNCI Cancer Spectr 2022; 6:6762867. [PMID: 36255251 PMCID: PMC9651977 DOI: 10.1093/jncics/pkac066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/09/2022] [Accepted: 09/16/2022] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Body mass index (BMI) during adulthood has been associated with pancreatic ductal adenocarcinoma (PDAC), however, patterns of body size across the adult life course have not been studied extensively. We comprehensively evaluated the association between adiposity across adulthood and PDAC. METHODS We conducted a prospective analysis of 269 480 (162 735 males, 106 745 females) National Institutes of Health-AARP Diet and Health Study participants, aged 50-71 years (1995-1996) who self-reported height and weight history. Participants were followed through December 31, 2011. We examined associations between BMI (kg/m2) at ages 18, 35, 50, and 50-71 (baseline) years, their trajectories determined from latent-class trajectory modeling, and incident PDAC. Cox proportional hazard models were used to calculate multivariable adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). RESULTS During up to 15.2 years of follow-up, 3092 (2020 males, 1072 females) patients with incident PDAC were identified. BMI at all 4 ages were statistically significantly associated with increased PDAC (per 5-unit increase, HR = 1.09-1.13) with higher magnitude associations in males than females at ages 35 years and older (Pinteraction < .05). Four BMI trajectories were created. Compared with normal-weight maintainers, normal-to-overweight, normal-to-obese class I, and overweight-to-obese class III trajectories had hazard ratios of 1.15 (95% CI = 1.06 to 1.25), 1.39 (95% CI = 1.25 to 1.54), and 1.48 (95% CI = 1.18 to 1.87), respectively (Pinteraction by sex = .07). CONCLUSIONS High BMI and BMI trajectories that result in overweight or obesity during adulthood were positively associated with PDAC, with stronger associations among those with early onset adiposity and those with male sex. Avoidance of excess body weight throughout the adult life course may prevent PDAC.
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Affiliation(s)
- Simran Arjani
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA,Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Pedro F Saint-Maurice
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Sachelly Julián-Serrano
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA,Department of Public Health, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, Lowell, MA, USA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA
| | - Rachael Stolzenberg-Solomon
- Correspondence to: Rachael Stolzenberg-Solomon, RD, MPH, PhD, Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, 9609 Medical Center Drive, NCI Shady Grove, Room 6E420, Rockville, MD 20850, USA (e-mail: )
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Afghani E, Klein AP. Pancreatic Adenocarcinoma: Trends in Epidemiology, Risk Factors, and Outcomes. Hematol Oncol Clin North Am 2022; 36:879-895. [PMID: 36154788 PMCID: PMC10548451 DOI: 10.1016/j.hoc.2022.07.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Pancreatic cancer is one of the most lethal cancers in the world; it is a silent disease in which symptoms do not present until advanced stages, thereby reducing the 5-year survival rate to 10%. The global burden of pancreatic cancer has doubled over the past 25 years despite advancements in medicine. This review aims to discuss the global trends and disparities in pancreatic cancer, as well as the up-to-date literature on the known risk factors. A better understanding of these risk factors will reduce mortality by providing opportunities to screen these patients as well as counseling on lifestyle modifications.
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Affiliation(s)
- Elham Afghani
- Johns Hopkins School of Medicine, 1830 E Monument Street, Room 436, Baltimore, MD 21205, USA
| | - Alison P Klein
- Johns Hopkins School of Medicine, 1830 E Monument Street, Room 436, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Johns Hopkins Bloomberg School of Public Health, 1550 Orleans Street, Baltimore, MD 21231, USA.
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Yun D, Yang Z, Zhang S, Yang H, Liu D, Grützmann R, Pilarsky C, Britzen-Laurent N. An m5C methylation regulator-associated signature predicts prognosis and therapy response in pancreatic cancer. Front Cell Dev Biol 2022; 10:975684. [PMID: 36060802 PMCID: PMC9437259 DOI: 10.3389/fcell.2022.975684] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/28/2022] [Indexed: 11/21/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive digestive malignancy due to frequent late-stage diagnosis, rapid progression and resistance to therapy. With increasing PDAC incidence worldwide, there is an urgent need for new prognostic biomarkers and therapy targets. Recently, RNA methylation has emerged as a new tumorigenic mechanism in different cancers. 5-methylcytosine (m5C) is one of the most frequent RNA modifications and occurs on a variety of RNA species including mRNA, thereby regulating gene expression. Here we investigated the prognostic role of m5C-regulator-associated transcriptional signature in PDAC. We evaluated m5C-regulator status and expression in 239 PDAC samples from publicly available datasets. We used unsupervised consensus clustering analyses to classify PDACs based on m5C-regulator expression. From the resulting signature of differentially expressed genes (DEGs), we selected prognosis-relevant DEGs to stratify patients and build a scoring signature (m5C-score) through LASSO and multivariate Cox regression analyses. The m5C-score represented a highly significant independent prognostic marker. A high m5C-score correlated with poor prognosis in different PDAC cohorts, and was associated with the squamous/basal subtype as well as activated cancer-related pathways including Ras, MAPK and PI3K pathways. Furthermore, the m5C-score correlated with sensitivity to pathway-specific inhibitors of PARP, EGFR, AKT, HER2 and mTOR. Tumors with high m5C-score were characterized by overall immune exclusion, low CD8+ T-cell infiltration, and higher PD-L1 expression. Overall, the m5C-score represented a robust predictor of prognosis and therapy response in PDAC, which was associated with unfavorable molecular subtypes and immune microenvironment.
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Affiliation(s)
- Duo Yun
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Zhirong Yang
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Shuman Zhang
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Hai Yang
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Dongxue Liu
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Robert Grützmann
- Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Pilarsky
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Nathalie Britzen-Laurent
- Division of Surgical Research, Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- *Correspondence: Nathalie Britzen-Laurent,
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Gili Ortiz E. Factors influencing mortality trends of pancreatic cancer in Spain, 1955-2020. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:474-480. [PMID: 35548865 DOI: 10.17235/reed.2022.8559/2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
OBJECTIVES The aim of this study was to analyze the trends of pancreatic cancer mortality in Spain from 1955-2020 in both genders and every age group, in order to describe the changes in the prevalence of some risk factors and their possible influence on mortality. METHODS Direct standardized mortality rates were calculated using the World Standard Population 2000-2025 and Joinpoint analysis was performed for age-specific and age-standardized mortality trends for the period from 1955-2020. RESULTS Mortality rates increased with age in both genders, with a marked increase in older groups. During 2020, 71.5% of male deaths and 81.5% of female deaths from pancreatic cancer occurred among those aged 65 years or more. Spanish National Health Surveys since 1987 show decreasing trends in daily smoking, but striking increases in obesity and diabetes mellitus rates in both genders, and rates of daily smoking and obesity are remarkably higher among disadvantaged social classes. CONCLUSIONS Pancreatic cancer mortality rates have increased uninterruptedly in Spain during the last decades. Increasing trends in obesity and diabetes mellitus, particularly among males, and the different prevalence of obesity and smoking according to social class are public health problems of great concern. Smoking and obesity are potentially avoidable risk factors. Thus, educational programs and legislative measures should be implemented more widely, such as programs for smoking prevention, healthy nutrition and physical exercise, and would be applied more intensively in the most disadvantaged social classes.
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Poman DS, Motwani L, Asif N, Patel A, Vedantam D. Pancreatic Cancer and the Obesity Epidemic: A Narrative Review. Cureus 2022; 14:e26654. [PMID: 35959181 PMCID: PMC9360631 DOI: 10.7759/cureus.26654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2022] [Indexed: 11/05/2022] Open
Abstract
Pancreatic cancer (PC) is one of the most frequent causes of death. It usually affects older individuals with incidence closely approaching mortality due to its early asymptomatic feature and highly metastatic nature. Multiple risk factors such as family history, smoking, and germline mutations are associated with PC development, with obesity being one of the controllable factors. This review article focuses on the compilation of various studies to help establish a correlation between obesity or an increased body mass index and PC development. Hence, in this review, we have summarised multiple biological mechanisms of PC development induced by obesity, including insulin resistance, inflammation, beta-cell dysfunction, and oxidative stress, to prove that their correlation when combined with other factors, such as smoking, alcohol and chronic pancreatitis, may increase its risk. We have also reviewed potential diagnostic and screening techniques, such as evaluating precancerous lesions in high-risk patients and management plans discussing upcoming advances in treatment tactics such as neoadjuvant therapy, to reduce post-operative complications.
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Affiliation(s)
| | - Lakshya Motwani
- Research and Development, Smt. Nathiba Hargovandas Lakhmichand (NHL) Municipal Medical College, Ahmedabad, IND
| | - Nailah Asif
- Research, Ras Al Khaimah (RAK) College of Medical Sciences, Ras Al Khaimah, ARE
| | - Apurva Patel
- Research, Gujarat Medical Education & Research Society (GMERS) Medical College, Gotri, Vadodara, IND
| | - Deepanjali Vedantam
- Internal Medicine, Kamineni Academy of Medical Sciences and Research Center, Hyderabad, IND
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Krill JT, Szafron D, Elhanafi S, Hussein MS, Patel K, Raijman I, Fisher W, El Serag HB, Othman MO. Endoscopic Ultrasound Finding of Diffuse Echogenicity in the Pancreas, Is It Relevant? Dig Dis Sci 2022; 67:3244-3251. [PMID: 34350519 DOI: 10.1007/s10620-021-07181-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 07/16/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND/OBJECTIVES Diffuse echogenicity of the pancreas, a commonly discovered finding on endoscopic ultrasound (EUS), is often of undetermined significance. The goal of this study was to characterize the clinical picture and pancreatic function in patients who incidentally present with this endosonographic finding. METHODS This was a case-control study comparing consecutive adult patients with diffuse echogenicity of the pancreas found on EUS to those who did not have known pancreas disease. Demographic and clinical data were extracted from the electronic medical record. The primary endpoint was exocrine pancreatic insufficiency (EPI) defined as fecal elastase (FE-1) < 200 μg/g. RESULTS A total of 166 patients were included in this study. There were 89 patients who had diffuse echogenicity of the pancreas on EUS and FE-1 testing. There were 77 control patients with chronic diarrhea who did not have known pancreas disease but did have FE-1 testing. EPI was significantly more likely in the fatty pancreas group compared to the control group (47% vs 6%, p < 0.001). There was also a significantly greater proportion of smokers in the fatty pancreas group compared to the control group (42% vs 17%, p = 0.002). There were no other differences in baseline characteristics between the two groups, including prevalence of chronic pancreatitis by Rosemont classification. On multiple logistic regression analysis controlling for multiple variables, smoking (OR 2.26, 95% CI 1.15-4.43) and NAFLD (OR 3.99, 95% CI 1.09-14.70) had significant associations with EPI. CONCLUSIONS This study found a significantly greater amount of patients who had diffuse echogenicity of the pancreas on EUS to also have EPI. This is compared to a control group of patients without known pancreas disease. This prevalence was found in the absence of a significant association with chronic pancreatitis on EUS based on Rosemont classification. Future controlled studies are required to further investigate this relationship.
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Affiliation(s)
- Joseph T Krill
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | - David Szafron
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Sherif Elhanafi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Mohammed S Hussein
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
- Department of Internal Medicine, Al-Azhar University, Cairo, Egypt
| | - Kalpesh Patel
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | | | - William Fisher
- Department of General Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Hashem B El Serag
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | - Mohamed O Othman
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA.
- Chief of Gastroenterology Section, Baylor St Luke's Medical Center, 7200 Cambridge St. STE 10C, Houston, TX, 77030, USA.
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Zakaria A, Al-Share B, Klapman JB, Dam A. The Role of Endoscopic Ultrasonography in the Diagnosis and Staging of Pancreatic Cancer. Cancers (Basel) 2022; 14:1373. [PMID: 35326524 PMCID: PMC8946253 DOI: 10.3390/cancers14061373] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer-related death and the second gastrointestinal cancer-related death in the United States. Early detection and accurate diagnosis and staging of pancreatic cancer are paramount in guiding treatment plans, as surgical resection can provide the only potential cure for this disease. The overall prognosis of pancreatic cancer is poor even in patients with resectable disease. The 5-year survival after surgical resection is ~10% in node-positive disease compared to ~30% in node-negative disease. The advancement of imaging studies and the multidisciplinary approach involving radiologists, gastroenterologists, advanced endoscopists, medical, radiation, and surgical oncologists have a major impact on the management of pancreatic cancer. Endoscopic ultrasonography is essential in the diagnosis by obtaining tissue (FNA or FNB) and in the loco-regional staging of the disease. The advancement in EUS techniques has made this modality a critical adjunct in the management process of pancreatic cancer. In this review article, we provide an overall description of the role of endoscopic ultrasonography in the diagnosis and staging of pancreatic cancer.
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Affiliation(s)
- Ali Zakaria
- Department of Gastroenterology-Advanced Endoscopy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (J.B.K.); (A.D.)
| | - Bayan Al-Share
- Department of Hematology and Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI 48201, USA;
| | - Jason B. Klapman
- Department of Gastroenterology-Advanced Endoscopy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (J.B.K.); (A.D.)
| | - Aamir Dam
- Department of Gastroenterology-Advanced Endoscopy, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; (J.B.K.); (A.D.)
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Wang X, Xu W, Hu X, Yang X, Zhang M. The Prognostic Role of Glycemia in Patients With Pancreatic Carcinoma: A Systematic Review and Meta-Analysis. Front Oncol 2022; 12:780909. [PMID: 35223469 PMCID: PMC8866248 DOI: 10.3389/fonc.2022.780909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/03/2022] [Indexed: 12/14/2022] Open
Abstract
Background Fasting blood glucose and glycated hemoglobin (HbA1c) levels are associated with the risk of pancreatic cancer. Aim To examine the relationship between perioperative glucose and HbA1c levels and prognosis in patients with pancreatic cancer. Methods PubMed, Embase, and the Cochrane Library were queried for potentially eligible studies published up to May 2021. The exposures were perioperative fasting glucose and HbA1c levels. The primary outcome was survival. The secondary outcome was complications. All analyses were performed using the random-effects model. Results Ten studies (48,424 patients) were included. The pre-operative (HR=1.10, 95%CI: 0.89-1.35; I2 = 45.1%, Pheterogeneity=0.078) and postoperative (HR=1.19, 95%CI: 0.92-1.54; I2 = 67.9%, Pheterogeneity=0.001) blood glucose levels were not associated with the survival to pancreatic cancer. Similar results were observed for HbA1c (HR=1.09, 95%CI: 0.75-1.58; I2 = 64.2%, Pheterogeneity=0.039), fasting blood glucose (FBG)/HbA1c (HR=1.16, 95%CI: 0.67-1.68; I2 = 0.0%, Pheterogeneity=0.928), and FBG (HR=1.75, 95%CI: 0.81-3.75; I2 = 79.4%, Pheterogeneity=0.008). Pre-operative blood glucose levels were not associated with postoperative complications (OR=0.90, 95%CI: 0.52-1.56), but postoperative glucose levels were associated with postoperative complications (OR=3.06, 95%CI: 1.88-4.97; I2 = 0.0%, Pheterogeneity=0.619). Conclusion Blood glucose, FBG, and HbA1c levels are not associated with the survival of patients with pancreatic cancer. Postoperative blood glucose levels could predict postoperative complications.
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Affiliation(s)
- Xiaofang Wang
- Department of Clinical Oncology and Department of Hospice Care, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wanfeng Xu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaoru Hu
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xianghong Yang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Mingming Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, China
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The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy. Cancers (Basel) 2022; 14:cancers14010217. [PMID: 35008381 PMCID: PMC8750069 DOI: 10.3390/cancers14010217] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma is a leading cause of cancer death worldwide. Due to the frequently late diagnosis, early metastasis and high therapy resistance curation is rare and prognosis remains poor overall. To provide early diagnostic and therapeutic predictors, various molecules from blood, tissue and other origin e.g., saliva, urine and stool, have been identified as biomarkers. This review summarizes current trends in biomarkers for diagnosis and therapy of pancreatic ductal adenocarcinoma. Abstract Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer.
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Rossmeislová L, Gojda J, Smolková K. Pancreatic cancer: branched-chain amino acids as putative key metabolic regulators? Cancer Metastasis Rev 2021; 40:1115-1139. [PMID: 34962613 DOI: 10.1007/s10555-021-10016-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/18/2021] [Indexed: 02/06/2023]
Abstract
Branched-chain amino acids (BCAA) are essential amino acids utilized in anabolic and catabolic metabolism. While extensively studied in obesity and diabetes, recent evidence suggests an important role for BCAA metabolism in cancer. Elevated plasma levels of BCAA are associated with an increased risk of developing pancreatic cancer, namely pancreatic ductal adenocarcinoma (PDAC), a tumor with one of the highest 1-year mortality rates. The dreadful prognosis for PDAC patients could be attributable also to the early and frequent development of cancer cachexia, a fatal host metabolic reprogramming leading to muscle and adipose wasting. We propose that BCAA dysmetabolism is a unifying component of several pathological conditions, i.e., obesity, insulin resistance, and PDAC. These conditions are mutually dependent since PDAC ranks among cancers tightly associated with obesity and insulin resistance. It is also well-established that PDAC itself can trigger insulin resistance and new-onset diabetes. However, the exact link between BCAA metabolism, development of PDAC, and tissue wasting is still unclear. Although tissue-specific intracellular and systemic metabolism of BCAA is being intensively studied, unresolved questions related to PDAC and cancer cachexia remain, namely, whether elevated circulating BCAA contribute to PDAC etiology, what is the biological background of BCAA elevation, and what is the role of adipose tissue relative to BCAA metabolism during cancer cachexia. To cover those issues, we provide our view on BCAA metabolism at the intracellular, tissue, and whole-body level, with special emphasis on different metabolic links to BCAA intermediates and the role of insulin in substrate handling.
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Affiliation(s)
- Lenka Rossmeislová
- Department of Pathophysiology, Center for Research On Nutrition, Metabolism, and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Franco-Czech Laboratory for Clinical Research On Obesity, Third Faculty of Medicine, Prague, Czech Republic
| | - Jan Gojda
- Franco-Czech Laboratory for Clinical Research On Obesity, Third Faculty of Medicine, Prague, Czech Republic
- Department of Internal Medicine, Královské Vinohrady University Hospital and Third Faculty of Medicine, Prague, Czech Republic
| | - Katarína Smolková
- Laboratory of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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