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Boubaddi M, Rossi J, Marichez A, Marty M, Amintas S, Laurent C, Dabernat S. Preoperative Prognostic Factors in Resectable Pancreatic Cancer: State of the Art and Prospects. Ann Surg Oncol 2025; 32:4117-4127. [PMID: 40095311 DOI: 10.1245/s10434-025-17062-w] [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: 12/20/2024] [Accepted: 02/09/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Only 15% to 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have access to surgical resection, which represents the only chance of curative treatment. Current resection classifications are almost exclusively anatomic and do not correlate sufficiently with patient survival. It is essential to develop preoperative prognostic factors to distinguish patients at high risk of early postoperative recurrence from those who will have prolonged survival after surgery. In some cases, PDACs may present biomolecular differences reflecting their aggressiveness that are not yet assessable by the current clinical-biologic assessment. This study aimed to assess the preoperative prognostic factors that are already available and the future perspectives being developed. METHOD This study reviewed the literature using the PubMed public database for preoperative prognostic factors for resectable PDAC. CONCLUSION Validated preoperative prognostic factors, whether clinical, biologic, radiologic, or histologic, are very important in anticipating the course of each patient's disease. The identification of potential new prognostic biomarkers such as genomic, transcriptomic, and proteomic analyses and the dosage of circulating tumor DNA are very serious avenues to be developed, but the extraction and analysis techniques as well as the interpretation of their results need to be standardized in prospective studies.
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Affiliation(s)
- Mehdi Boubaddi
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France.
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France.
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital, Bordeaux, France.
| | - Julia Rossi
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Arthur Marichez
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Marion Marty
- Tumor Biology and Tumor Bank Laboratory, CHU Bordeaux, Bordeaux, France
| | - Samuel Amintas
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
| | - Christophe Laurent
- Colorectal Unit, Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
| | - Sandrine Dabernat
- BRIC (BoRdeaux Institute of onCology), UMR1312, INSERM, University of Bordeaux, Bordeaux, France
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Gonzalo-Encabo P, Gardiner J, Norris MK, Wilson RL, Normann AJ, Nguyen D, Parker N, Tjogas D, Brais LK, Meyerhardt JA, Rosenthal MH, Wolpin BM, Uno H, Dieli-Conwright CM. Resistance exercise combined with protein supplementation for skeletal muscle mass in people with pancreatic cancer undergoing neoadjuvant chemotherapy: Study protocol for the REBUILD trial. PLoS One 2025; 20:e0322192. [PMID: 40315221 PMCID: PMC12047797 DOI: 10.1371/journal.pone.0322192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 03/10/2025] [Indexed: 05/04/2025] Open
Abstract
BACKGROUND Pancreatic cancer patients' prognosis may be limited by two conditions, cachexia and sarcopenia. Resistance exercise and protein supplementation are safe non-pharmacological strategies that may increase or preserve skeletal muscle mass within this population. Therefore, the primary aim of this study is to examine the feasibility of a home-based virtually supervised resistance exercise intervention, with or without protein supplementation in pancreatic cancer patients initiating neoadjuvant chemotherapy. This intervention may also maintain skeletal muscle mass and improve plasma biomarkers associated with muscle tissue wasting, physical function and psychological measures. METHODS We aim to recruit 45 patients with locally advanced pancreatic cancer initiating neoadjuvant chemotherapy. Patients will be randomized to receive either Resistance Exercise (RE) (n = 15), Resistance Exercise and Protein Supplementation (RE + PS) (n = 15), or Attention Control (AC) (n = 15). Patients randomized to RE or RE + PS will receive 16-weeks of home-based virtually supervised resistance exercise. The AC will receive a 16-week stretching program. Primary and secondary outcomes will be measured at baseline and after 16 weeks during study visits. DISCUSSION The REBUILD trial is the first randomized controlled trial that combines resistance exercise with daily protein supplementation during neoadjuvant chemotherapy in pancreatic cancer patients. Our novel home-based virtually supervised exercise intervention seeks to mitigate barriers to participation in this vulnerable population. Furthermore, results of this trial will address important research gaps associated with pancreatic cancer-related cachexia, a condition closely connected with poor prognosis and mortality.
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Affiliation(s)
- Paola Gonzalo-Encabo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
- Departamento de Ciencias Biomédicas, Área de Educación Física y Deportiva, Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá, Madrid, España
| | - John Gardiner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Mary K. Norris
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Rebekah L. Wilson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Amber J. Normann
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Health Sciences, Boston University, Boston, Massachusetts, United States of America
| | - Danny Nguyen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Nathan Parker
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, United States of America
| | - Darryl Tjogas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Lauren K. Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Jeffrey A. Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Michael H. Rosenthal
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
- Department of Imaging, Dana-Farber Cancer Institute, Boston Massachusetts, United States of America
- Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
| | - Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Hajime Uno
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Christina M. Dieli-Conwright
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
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Chen X, Chen X, Zhao X, Pang X, Dai M, Sun Y, Wang M, Han J, Zhao Y. Subcutaneous adipose tissue [ 18F]FDG uptake and CT-derived body composition variables for predicting survival outcomes in patients with locally advanced gastric cancer. Eur J Nucl Med Mol Imaging 2025:10.1007/s00259-025-07296-x. [PMID: 40272500 DOI: 10.1007/s00259-025-07296-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 04/21/2025] [Indexed: 04/25/2025]
Abstract
PURPOSE This study aimed to investigate the impact of glucose metabolism in subcutaneous adipose tissue (SAT) and skeletal muscle (SM) variables on overall survival (OS) in patients with locally advanced gastric cancer. METHODS A retrospective study was conducted on 110 patients with advanced gastric cancer who underwent baseline [18F]FDG PET/CT. Demographic, clinical, and survival data were collected. Mean standardized uptake value (SUVmean) of SAT as well as skeletal muscle, and body composition measurement, including SAT area, SAT radiodensity, SM area, and SM radiodensity, were assessed on PET/CT. SM area was normalized for patient stature, resulting in the skeletal muscle index (SMI). Patients were stratified into subgroups with high and low SAT uptake based on the optimum cut-off value of the SAT SUVmean. The univariate, multivariate regression analysis, Kaplan-Meier survival analysis, and Spearman's correlation analysis were employed to evaluate the associations among metabolic activity and CT-derived body composition variables as well as OS. RESULTS Out of 110 patients with an average age of 62.65 ± 13.25 years, 58 (52.73%) patients died during follow-up. Cox regression analysis identified TNM stage, SAT SUVmean, and SMI as independent prognostic factors for OS (all p < 0.05). Notably, patients with elevated SAT uptake exhibited significantly poorer long-term survival compared to those with low SAT uptake (p < 0.001). Correlation analyses revealed a moderate positive association between SAT SUVmean and SAT radiodensity (p < 0.001, r = 0.47), whereas a significant inverse correlation was observed between SAT SUVmean and SAT area (p < 0.001, r = -0.465). Additionally, stratification by combined SAT SUVmean and SMI profiles showed that patients with low SAT uptake and high SMI exhibited a better prognosis than those with high SAT uptake and/or low SMI (p = 0.004 and p < 0.001). CONCLUSION Increased [18F]FDG uptake in SAT was correlated with higher SAT radiodensity as well as lower SAT area, and shortened survival in patients with advanced gastric cancer, underscoring its potential as a biomarker for adverse outcomes.
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Affiliation(s)
- Xiaoshan Chen
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China
| | - Xiaolin Chen
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China
| | - Xinming Zhao
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China.
- Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, Hebei, 050011, China.
| | - Xiao Pang
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China
| | - Meng Dai
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China
| | - Yuhan Sun
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China
| | - Mengjiao Wang
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China
| | - Jingya Han
- Department of Nuclear Medicine, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, China
- Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Shijiazhuang, Hebei, 050011, China
| | - Yan Zhao
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China.
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Shahbaz SK, Mokhlesi A, Sadegh RK, Rahimi K, Jamialahmadi T, Butler AE, Kesharwani P, Sahebkar A. TLR/NLRP3 inflammasome signaling pathways as a main target in frailty, cachexia and sarcopenia. Tissue Cell 2025; 93:102723. [PMID: 39823704 DOI: 10.1016/j.tice.2025.102723] [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: 11/07/2024] [Revised: 12/28/2024] [Accepted: 01/03/2025] [Indexed: 01/20/2025]
Abstract
Mobility disability is a common condition affecting older adults, making walking and the performance of activities of daily living difficult. Frailty, cachexia and sarcopenia are related conditions that occur with advancing age and are characterized by a decline in muscle mass, strength, and functionality that negatively impacts health. Chronic low-grade inflammation is a significant factor in the onset and progression of these conditions. The toll-like receptors (TLRs) and the NLRP3 inflammasome are the pathways of signaling that regulate inflammation. These pathways can potentially be targeted therapeutically for frailty, cachexia and sarcopenia as research has shown that dysregulation of the TLR/NLRP3 inflammasome signaling pathways is linked to these conditions. Activation of TLRs with pathogen-associated molecular patterns (PAMPs or DAMPs) results in chronic inflammation and tissue damage by releasing pro-inflammatory cytokines. Additionally, NLRP3 inflammasome activation enhances the inflammatory response by promoting the production and release of interleukins (ILs), thus exacerbating the underlying inflammatory mechanisms. These pathways are activated in the advancement of disease in frail and sarcopenic individuals. Targeting these pathways may offer therapeutic options to reduce frailty, improve musculoskeletal resilience and prevent or reverse cachexia-associated muscle wasting. Modulating TLR/NLRP3 inflammasome pathways may also hold promise in slowing down the progression of sarcopenia, preserving muscle mass and enhancing overall functional ability in elderly people. The aim of this review is to investigate the signaling pathways of the TLR/NLRP3 inflammasome as a main target in frailty, cachexia and sarcopenia.
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Affiliation(s)
- Sanaz Keshavarz Shahbaz
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Aida Mokhlesi
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; Social Determinants of Health Research Center, Research Institute for Prevention of Non-communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical Sciences, Qazvin, Iran; Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Roghaye Keshavarz Sadegh
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Kimia Rahimi
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran; USERN Office, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Tannaz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Amirhossein Sahebkar
- Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Xu X, Tian M, Ding CC, Xu H, Wang H, Jin X. Skeletal Muscle Index-Based Cachexia Index as a Predictor of Prognosis in Patients With Cancer: A Meta-Analysis and Systematic Review. Nutr Rev 2025; 83:e852-e865. [PMID: 39001797 DOI: 10.1093/nutrit/nuae094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/15/2024] Open
Abstract
CONTEXT Cachexia is associated with poor survival rates. In the clinical setting, the diagnosis of cancer cachexia is challenging. The cachexia index (CXI), a new index for predicting survival time, is a promising tool for diagnosing cancer cachexia; however, its efficacy in predicting patient survival has not been validated. OBJECTIVE This meta-analysis and systematic review aimed to explore the CXI's prognostic value in patients with cancer. DATA SOURCES The PubMed, Embase, MEDLINE, and Cochrane Library databases were searched for relevant studies to determine the association between CXI findings and prognosis. DATA EXTRACTION The outcomes were overall survival (OS), progression-, disease-, and recurrence-free survival (PFS/DFS/RFS) rates, and the rate of complete response. DATA ANALYSIS The QUality In Prognostic Studies (QUIPS) tool was used to evaluate the quality of the included trials. This meta-analysis comprised 14 studies involving 2777 patients. A low CXI was associated with decreased OS (hazard ratio [HR] 2.34, 95% confidence interval [CI] 2.01-2.72; P < .001), PFS/DFS/RFS (HR 1.93, 95% CI 1.68-2.22; P < .001), and complete response (odds ratio [OR] 0.49, 95% CI 0.36-0.66; P < .001). Patients with a low CXI had a lower body mass index (mean difference [MD] -0.75, 95% CI -1.00 to 0.50; P < .001), skeletal muscle index (standardized MD -0.80, 95% CI -0.98 to -0.61; P < .001), and serum albumin level (MD -0.23, 95% CI -0.26 to -0.20; P < .001); and a higher neutrophil-lymphocyte ratio (MD 1.88, 95% CI 1.29-2.47; P < .001) and more advanced disease stages (OR 0.80, 95% CI 0.71-0.91; P = .001). CONCLUSION A low CXI was found to be associated with poor survival in patients with cancer. While the CXI is a promising marker for predicting cancer cachexia, further studies are required to verify its usefulness.
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Affiliation(s)
- Xintian Xu
- Department of Pharmacy, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Mengxing Tian
- Department of Clinical Nutrition, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Chen Chen Ding
- Department of Clinical Nutrition, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Huiting Xu
- Department of Abdominal Oncology 1, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Huifen Wang
- Nursing Department, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Xin Jin
- Department of Clinical Nutrition, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
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Chang PJ, Hendifar AE, Gresham G, Ngo-Huang A, Oberstein PE, Parker N, Coveler AL. Exercise Guidelines in Pancreatic Cancer Based on the Dietz Model. Cancers (Basel) 2025; 17:630. [PMID: 40002225 PMCID: PMC11853477 DOI: 10.3390/cancers17040630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/07/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Pancreatic and gastrointestinal cancers are associated with debility, frailty, and chemotherapy regiments with significant toxicity. Practical exercise guidelines to combat these ailments and optimize functional status are lacking. We present a model for exercise for these cancers based on the Dietz framework for rehabilitation in cancer. The Dietz framework for rehabilitation describes four phases of rehabilitation including preventative (prehabilitation), restorative, supportive, and palliative. We present practical guidelines for exercise at each phase. Prehabilitation seeks to optimize functional performance typically prior to surgical resection and may occur concurrently with neoadjuvant therapy. Restorative rehabilitation occurs following the development of a physical deficit such as after surgery and may utilize skilled therapies in the inpatient, subacute, outpatient, and home settings to address functional impairments. Supportive rehabilitation occurs during stable disease or remission and depends on the frequent monitoring of functional status and particularly the development of chemotherapy-induced neuropathy to ensure timely exercise interventions. Palliative rehabilitation occurs at the end stage of life and shifts to a focus on patient comfort and safety. Exercise is a critical component of treatment in cancer demonstrating numerous quality-of-life benefits. The customization of exercise recommendations to individual patients based on their functional status and phase in treatment is essential for safety and adherence.
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Affiliation(s)
| | | | | | - An Ngo-Huang
- MD Anderson Cancer Center, Houston, TX 77030, USA
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Park S, Choi GW, Lee I, Seo Y, Chae YS, Yun WG, Han Y, Jung HS, Kwon W, Park JS, Jang JY, Cho YJ. Impact of Nutritional Changes on the Prognosis in Pancreatic Cancer Patients Underwent Curative Surgery After Neoadjuvant Chemotherapy. Nutrients 2025; 17:647. [PMID: 40004975 PMCID: PMC11858578 DOI: 10.3390/nu17040647] [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: 01/14/2025] [Revised: 02/09/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Pancreatic cancer is a highly aggressive malignancy with a poor prognosis. Neoadjuvant chemotherapy (NAC) is increasingly used to improve survival in patients with pancreatic cancer; however, it often results in nutritional deterioration, which may negatively impact patient outcomes. Therefore, this study aimed to assess the effect of changes in nutritional status on the long-term outcomes of patients with pancreatic cancer who underwent curative surgery after NAC. METHODS This retrospective single-center study included 148 patients with pancreatic cancer who underwent curative surgery after NAC between 2010 and 2020. The Controlled Nutritional Status (CONUT) score was used to determine the nutritional status of the patients. Patients were categorized into worsened, maintained, and improved groups based on the changes in their CONUT scores before and after NAC. We compared differences in overall survival (OS) and disease-free survival (DFS) between the groups. RESULTS The worsened nutritional status group exhibited the shortest median OS (28 months) compared to the maintained and improved groups (39 and 66 months, respectively; p = 0.01). Additionally, the worsened group demonstrated the shortest DFS compared to the other two groups (13, 22, and 39 months, respectively; p = 0.02). Multivariate analysis identified nutritional deterioration as an independent prognostic factor for OS (hazard ratios (HR), 2.11; 95% confidence intervals (CI), 1.31-3.40; p < 0.01). CONCLUSIONS Nutritional deterioration after NAC is a significant prognostic factor of poor survival outcomes in patients with pancreatic cancer. These findings indicate that serial nutritional assessments and treatment during NAC are crucial for improving patient outcomes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Young Jae Cho
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; (S.P.); (G.-W.C.); (I.L.); (Y.S.); (Y.S.C.); (W.-G.Y.); (Y.H.); (H.-S.J.); (W.K.); (J.S.P.); (J.-Y.J.)
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Neyroud D, D'Lugos A, Trevino E, Callaway C, Lamm J, Laitano O, Poole B, Deyhle M, Brantley J, Le L, Judge A, Judge S. Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer. J Cachexia Sarcopenia Muscle 2025; 16:e13668. [PMID: 39810606 PMCID: PMC11733308 DOI: 10.1002/jcsm.13668] [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: 07/29/2024] [Revised: 10/16/2024] [Accepted: 11/06/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia. METHODS To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint). RESULTS During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8-endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10-endpoint vs. Sham, p < 0.05), fibre atrophy (-16% to -24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8-fold; D14-endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (-55%, p = 0.0074) and diaphragm excursion (-43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation. CONCLUSIONS In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.
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Affiliation(s)
- Daria Neyroud
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
- Institute of Sports SciencesUniversity of LausanneLausanneSwitzerland
| | - Andrew C. D'Lugos
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
| | - Enrique J. Trevino
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
| | - Chandler S. Callaway
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
| | - Jacqueline Lamm
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
| | - Orlando Laitano
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
- Department of Applied Physiology and KinesiologyUniversity of FloridaGainesvilleFloridaUSA
| | - Brittney Poole
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
- Department of Physiology and Aging, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Michael R. Deyhle
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
| | - Justina Brantley
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
| | - Lam Le
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
| | - Andrew R. Judge
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
- Department of Physiology and Aging, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
| | - Sarah M. Judge
- Department of Physical TherapyUniversity of Florida Health Cancer CenterGainesvilleFloridaUSA
- Myology InstituteUniversity of FloridaGainesvilleFloridaUSA
- Department of Physiology and Aging, College of MedicineUniversity of FloridaGainesvilleFloridaUSA
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Jiang Y, Huang M, Zhao Y, Dai J, Yang Q, Tang X, Li X, Cui Y, Zhang J, Sun J, Fu L, Mao H, Peng XG. A [ 18F]FDG PET based nomogram to predict cancer-associated cachexia and survival outcome: A multi-center study. Nutrition 2025; 129:112593. [PMID: 39426212 DOI: 10.1016/j.nut.2024.112593] [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: 04/16/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/21/2024]
Abstract
OBJECTIVES Cancer patients with cachexia face poor prognosis and shortened survival. Early diagnosis and accurate prognosis prediction remain challenging. This multi-center study aims to develop and externally validate a nomogram integrating [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET findings and routine clinical biochemistry tests for predicting cancer-associated cachexia, while also assessing its potential prognostic value. RESEARCH METHODS & PROCEDURES A retrospective analysis of 658 cancer patients (390 in the development cohort, 268 in the validation cohort) utilized [18F]FDG PET/CT data from two centers. Logistic regression identified organ-specific standardized uptake values (SUVs) and clinical variables associated with cancer-associated cachexia. Diagnostic accuracy, discriminative ability, and clinical effectiveness were assessed using area under the curve (AUC), calibration curve, and decision curve. Nomogram predictability for overall survival was evaluated through Cox regression and Kaplan-Meier curves. RESULTS The combined nomogram incorporating age (odds ratio [OR] = 1.893; P = 0.012), hemoglobin (OR = 2.591; P < 0.001), maximum SUV of the liver (OR = 3.646; P < 0.001), and minimum SUV of the subcutaneous fat (OR = 5.060; P < 0.001) achieved good performance in predicting cancer-associated cachexia (AUC = 0.807/0.726, development/validation). Calibration and decision curve analyses confirmed its clinical effectiveness. Kaplan-Meier curves analysis showed that overall survival can be categorized using the combined nomogram (P < 0.001). CONCLUSION Combining radiological information from clinical standard [18F]FDG PET data from cancer patients with biochemical results in their routine clinical blood tests through a well-constructed nomogram enables predicting cachexia and its effect on the prognosis of cancer patients.
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Affiliation(s)
- Yang Jiang
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Mouqing Huang
- Department of Nuclear Medicine, Ganzhou People's Hospital, Ganzhou, China
| | - Yufei Zhao
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jingyue Dai
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Qingwen Yang
- Department of Internal Medicine, Ulm University & Ulm University Hospital, Ulm, Germany
| | - Xingzhe Tang
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xinxiang Li
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ying Cui
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jingqi Zhang
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jialu Sun
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Lin Fu
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hui Mao
- Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia, USA
| | - Xin-Gui Peng
- Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Radiology, Nanjing Lishui People's Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, China.
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10
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Ye WK, Wang J, Zheng J, Jiang M, Zhou YN, Wu ZX. Predictive value of the nutritional risk index for postoperative complications in individuals with pancreatic cancer undergoing pancreaticoduodenectomy. Geriatr Nurs 2025; 61:605-612. [PMID: 39778421 DOI: 10.1016/j.gerinurse.2024.12.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 12/10/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE To explore the predictive value of the geriatric nutritional risk index (GNRI) for postoperative complications and their severity in older adults with pancreatic cancer undergoing pancreaticoduodenectomy (PD). METHODS This study conducted a retrospective analysis of 109 older adults with pancreatic cancer undergoing PD at the Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Quzhou Medical University, between May 2019 and May 2022. Statistical analysis of clinical data was performed to assess the predictive value of the GNRI for postoperative complications and their severity in older adults with pancreatic cancer undergoing PD. RESULTS Among the 109 individuals in this study, a total of 41 older adults undergoing PD experienced postoperative complications. The outcomes of the regression analysis showed that preoperative GNRI (OR = 0.184, 95 % CI = 0.023-0.457, P < 0.001), albumin levels (OR = 0.897, 95 % CI = 0.812-0.912, P < 0.001) and haemoglobin levels (OR = 1.231, 95 % CI = 1.043-1.451, P = 0.034) significantly influence the incidence of postoperative complications in older adults with pancreatic cancer. The prognostic value of the GNRI in predicting overall postoperative complications boasts a sensitivity of 83.2 %, specificity of 71.2 %, positive predictive value of 81.1 %, negative predictive value of 65.9 %, accuracy rate of 73.1 %, area under the curve (AUC) of 0.756 (P < 0.001) and a discriminative threshold of 97.0. Furthermore, the predictive efficacy of the GNRI in gauging the severity of postoperative complications demonstrates a sensitivity of 85.32 % and specificity of 79.54 %. CONCLUSION The GNRI can offer a faster, simpler and more effective method for evaluating nutritional risk in individuals with pancreatic tumours. Moreover, for older adults undergoing PD, it can serve as a convenient and efficient nutritional predictive indicator for postoperative complications and their severity.
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Affiliation(s)
- Wei Kang Ye
- Department of Pancreatic Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, ZheJiang 324000, PR China
| | - Jin Wang
- Department of Pancreatic Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, ZheJiang 324000, PR China
| | - Jie Zheng
- Department of Pancreatic Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, ZheJiang 324000, PR China
| | - Ming Jiang
- Department of Pancreatic Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, ZheJiang 324000, PR China
| | - Yi Nong Zhou
- Department of Pancreatic Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, ZheJiang 324000, PR China
| | - Zhi Xiang Wu
- Department of Emergency Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, ZheJiang 324000, PR China.
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11
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Ji Jang H, Soo Lee S, Baek S, Jeong B, Wook Kim D, Hee Kim J, Jung Kim H, Ho Byun J, Lee W, Cheol Kim S. Prognostic implication of extra-pancreatic organ invasion in resectable pancreas ductal adenocarcinoma in the pancreas tail. Eur J Radiol 2024; 181:111715. [PMID: 39241306 DOI: 10.1016/j.ejrad.2024.111715] [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: 06/24/2024] [Revised: 07/26/2024] [Accepted: 08/31/2024] [Indexed: 09/09/2024]
Abstract
OBJECTIVES To assess the prognostic significance of extra-pancreatic organ invasion in patients with resectable pancreatic ductal adenocarcinoma (PDAC) in the pancreas tail. MATERIALS & METHODS This retrospective study included patients with resectable PDAC in the pancreas tail who received upfront surgery between 2014 and 2020 at a tertiary institution. Preoperative pancreas protocol computed tomography (CT) scans evaluated tumor size, peripancreatic tumor infiltration, suspicious metastatic lymph nodes, and extra-pancreatic organ invasion. The influence of extra-pancreatic organ invasion, detected by CT or postoperative pathology, on pathologic resection margin status was evaluated using logistic regression. The impact on recurrence-free survival (RFS) was analyzed using multivariable Cox proportional hazard models (clinical-CT and clinical-pathologic). RESULTS The study included 158 patients (mean age, 65 years ± 8.8 standard deviation; 93 men). Extra-pancreatic organ invasion identified by either CT (p = 0.92) or pathology (p = 0.99) was not associated with a positive resection margin. Neither CT (p = 0.42) nor pathological (p = 0.64) extra-pancreatic organ invasion independently correlated with RFS. Independent predictors for RFS included suspicious metastatic lymph node (hazard ratio [HR], 2.05; 95 % confidence interval [CI], 1.08-3.9; p = 0.03) on CT in the clinical-CT model, pathological T stage (HR, 2.97; 95 % confidence interval [CI], 1.39-6.35; p = 0.005 for T2 and HR, 3.78; 95 % CI, 1.64-8.76; p = 0.002 for T3) and adjuvant therapy (HR, 0.62; 95 % confidence interval [CI], 0.42-0.92; p = 0.02) in the clinical-pathologic model. CONCLUSION Extra-pancreatic organ invasion does not independently influence pathologic resection margin status and RFS in patients with resectable PDAC in the pancreas tail after curative-intent resection; therefore, it should not be considered a high-risk factor.
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Affiliation(s)
- Hyeon Ji Jang
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Seung Soo Lee
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
| | - Seunghee Baek
- Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Boryeong Jeong
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Dong Wook Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jin Hee Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Hyoung Jung Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jae Ho Byun
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Woohyung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
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12
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Pryce BR, Oles A, Talbert EE, Romeo MJ, Vaena S, Sharma S, Spadafora V, Tolliver L, Mahvi DA, Morgan KA, Lancaster WP, Beal E, Koren N, Watts B, Overstreet M, Berto S, Subramanian S, Calisir K, Crawford A, Neelon B, Ostrowski MC, Zimmers TA, Tidball JG, Wang DJ, Guttridge DC. Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia. Cell Rep 2024; 43:114925. [PMID: 39475511 PMCID: PMC11774514 DOI: 10.1016/j.celrep.2024.114925] [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: 10/14/2023] [Revised: 07/01/2024] [Accepted: 10/14/2024] [Indexed: 12/01/2024] Open
Abstract
Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB+ cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB+ cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
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Affiliation(s)
- Benjamin R Pryce
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Alexander Oles
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Erin E Talbert
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Health and Human Physiology, and the Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Martin J Romeo
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Silvia Vaena
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Sudarshana Sharma
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Victoria Spadafora
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Lauren Tolliver
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - David A Mahvi
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Katherine A Morgan
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - William P Lancaster
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Eryn Beal
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Natlie Koren
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Bailey Watts
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Morgan Overstreet
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29403, USA
| | - Stefano Berto
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Suganya Subramanian
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Kubra Calisir
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Anna Crawford
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Brian Neelon
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Michael C Ostrowski
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Teresa A Zimmers
- Department of Cell, Developmental, and Cancer Biology, Knight Cancer Institute, Portland, Oregon Health Science University, Portland, OR 97239, USA
| | - James G Tidball
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - David J Wang
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Denis C Guttridge
- Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
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13
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Yule MS, Brown LR, Waller R, Wigmore SJ. Cancer cachexia. BMJ 2024; 387:e080040. [PMID: 39442934 DOI: 10.1136/bmj-2024-080040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Affiliation(s)
- Michael S Yule
- St Columba's Hospice, Edinburgh EH5 3RW, UK
- Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Leo R Brown
- Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK
| | - Rachel Waller
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
| | - Stephen J Wigmore
- Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK
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14
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Stelter K, Alabssi A, Bonaterra GA, Schwarzbach H, Fendrich V, Slater EP, Kinscherf R, Hildebrandt W. Increased Myocardial MAO-A, Atrogin-1, and IL-1β Expression in Transgenic Mice with Pancreatic Carcinoma-Benefit of MAO-A Inhibition for Cardiac Cachexia. Biomedicines 2024; 12:2009. [PMID: 39335522 PMCID: PMC11428447 DOI: 10.3390/biomedicines12092009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/23/2024] [Accepted: 08/28/2024] [Indexed: 09/30/2024] Open
Abstract
Cancer cachexia (CC) continues to challenge clinicians by massively impairing patients' prognosis, mobility, and quality of life through skeletal muscle wasting. CC also includes cardiac cachexia as characterized by atrophy, compromised metabolism, innervation and function of the myocardium through factors awaiting clarification for therapeutic targeting. Because monoamine oxidase-A (MAO-A) is a myocardial source of H2O2 and implicated in myofibrillar protein catabolism and heart failure, we presently studied myocardial MAO-A expression, inflammatory cells, and capillarization together with transcripts of pro-inflammatory, -angiogenic, -apoptotic, and -proteolytic signals (by qRT-PCR) in a 3x-transgenic (LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre) mouse model of orthotopic pancreatic ductal adenoarcinoma (PDAC) compared to wild-type (WT) mice. Moreover, we evaluated the effect of MAO-A inhibition by application of harmine hydrochloride (HH, 8 weeks, i.p., no sham control) on PDAC-related myocardial alterations. Myocardial MAO-A protein content was significantly increased (1.69-fold) in PDAC compared to WT mice. PDAC was associated with an increased percentage of atrogin-1+ (p < 0.001), IL-1β+ (p < 0.01), COX2+ (p < 0.001), and CD68+ (p > 0.05) cells and enhanced transcripts of pro-inflammatory IL-1β (2.47-fold), COX2 (1.53-fold), TNF (1.87-fold), and SOCS3 (1.64-fold). Moreover, PDAC was associated with a reduction in capillary density (-17%, p < 0.05) and transcripts of KDR (0.46-fold) but not of VEGFA, Notch1, or Notch3. Importantly, HH treatment largely reversed the PDAC-related increases in atrogin-1+, IL-1β+, and TNF+ cell fraction as well as in COX2, IL-1β, TNF, and SOCS3 transcripts, whereas capillary density and KDR transcripts failed to improve. In mice with PDAC, increased myocardial pro-atrophic/-inflammatory signals are attributable to increased expression of MAO-A, because they are significantly improved with MAO-A inhibition as a potential novel therapeutic option. The PDAC-related loss in myocardial capillary density may be due to other mechanisms awaiting evaluation with consideration of cardiomyocyte size, cardiac function and physical activity.
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Affiliation(s)
- Kira Stelter
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, 35032 Marburg, Germany; (K.S.); (A.A.); (G.A.B.); (H.S.); (R.K.)
| | - Annalena Alabssi
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, 35032 Marburg, Germany; (K.S.); (A.A.); (G.A.B.); (H.S.); (R.K.)
| | - Gabriel Alejandro Bonaterra
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, 35032 Marburg, Germany; (K.S.); (A.A.); (G.A.B.); (H.S.); (R.K.)
| | - Hans Schwarzbach
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, 35032 Marburg, Germany; (K.S.); (A.A.); (G.A.B.); (H.S.); (R.K.)
| | - Volker Fendrich
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University of Marburg, 35032 Marburg, Germany; (V.F.); (E.P.S.)
| | - Emily P. Slater
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps-University of Marburg, 35032 Marburg, Germany; (V.F.); (E.P.S.)
| | - Ralf Kinscherf
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, 35032 Marburg, Germany; (K.S.); (A.A.); (G.A.B.); (H.S.); (R.K.)
| | - Wulf Hildebrandt
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, 35032 Marburg, Germany; (K.S.); (A.A.); (G.A.B.); (H.S.); (R.K.)
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15
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Zhang Y, Dos Santos M, Huang H, Chen K, Iyengar P, Infante R, Polanco PM, Brekken RA, Cai C, Caijgas A, Cano Hernandez K, Xu L, Bassel-Duby R, Liu N, Olson EN. A molecular pathway for cancer cachexia-induced muscle atrophy revealed at single-nucleus resolution. Cell Rep 2024; 43:114587. [PMID: 39116208 PMCID: PMC11472345 DOI: 10.1016/j.celrep.2024.114587] [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: 02/14/2024] [Revised: 05/14/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024] Open
Abstract
Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.
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Affiliation(s)
- Yichi Zhang
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Matthieu Dos Santos
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Huocong Huang
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kenian Chen
- Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Puneeth Iyengar
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Rodney Infante
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Patricio M Polanco
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Rolf A Brekken
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Chunyu Cai
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ambar Caijgas
- Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Karla Cano Hernandez
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lin Xu
- Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Rhonda Bassel-Duby
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ning Liu
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Eric N Olson
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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16
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Jones AJ, Novinger LJ, Bonetto A, Davis KP, Giuliano MM, Mantravadi AV, Sim MW, Moore MG, Yesensky JA. Histopathologic Features of Mucosal Head and Neck Cancer Cachexia. Int J Surg Oncol 2024; 2024:5339292. [PMID: 38966634 PMCID: PMC11223910 DOI: 10.1155/2024/5339292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 03/16/2024] [Accepted: 06/05/2024] [Indexed: 07/06/2024] Open
Abstract
Objective Determine the histopathologic features that correlate with head and neck cancer (HNC) cachexia. Methods A single-institution, retrospective study was performed on adults with HPV-negative, mucosal squamous cell carcinoma of the aerodigestive tract undergoing resection and free flap reconstruction from 2014 to 2019. Patients with distant metastases were excluded. Demographics, comorbidities, preoperative nutrition, and surgical pathology reports were collected. Comparisons of histopathologic features and cachexia severity were made. Results The study included 222 predominantly male (64.9%) patients aged 61.3 ± 11.8 years. Cachexia was identified in 57.2% patients, and 18.5% were severe (≥15% weight loss). No differences in demographics were identified between the groups. Compared to control, patients with severe cachexia had lower serum hemoglobin (p=0.048) and albumin (p < 0.001), larger tumor diameter (p < 0.001), greater depth of invasion (p < 0.001), and elevated proportions of pT4 disease (p < 0.001), pN2-N3 disease (p=0.001), lymphovascular invasion (p=0.009), and extranodal extension (p=0.014). Multivariate logistic regression identified tumor size (OR [95% CI] = 1.36 [1.08-1.73]), oral cavity tumor (OR [95% CI] = 0.30 [0.11-0.84]), and nodal burden (OR [95% CI] = 1.16 [0.98-1.38]) as significant histopathologic contributors of cancer cachexia. Conclusions Larger, more invasive tumors with nodal metastases and aggressive histologic features are associated with greater cachexia severity in mucosal HNC.
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Affiliation(s)
- Alexander J. Jones
- Indiana University School of MedicineDepartment of Otolaryngology-Head & Neck Surgery, Indianapolis, IN, USA
| | - Leah J. Novinger
- University of Colorado AnschutzDepartment of Pathology, Aurora, CO, USA
| | - Andrea Bonetto
- University of Colorado AnschutzDepartment of Pathology, Aurora, CO, USA
| | - Kyle P. Davis
- St. Louis University School of MedicineDepartment of Otolaryngology-Head & Neck Surgery, St. Louis, MO, USA
| | - Marelle M. Giuliano
- Indiana University School of MedicineDepartment of Otolaryngology-Head & Neck Surgery, Indianapolis, IN, USA
| | - Avinash V. Mantravadi
- Indiana University School of MedicineDepartment of Otolaryngology-Head & Neck Surgery, Indianapolis, IN, USA
| | - Michael W. Sim
- Indiana University School of MedicineDepartment of Otolaryngology-Head & Neck Surgery, Indianapolis, IN, USA
| | - Michael G. Moore
- Indiana University School of MedicineDepartment of Otolaryngology-Head & Neck Surgery, Indianapolis, IN, USA
| | - Jessica A. Yesensky
- Indiana University School of MedicineDepartment of Otolaryngology-Head & Neck Surgery, Indianapolis, IN, USA
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17
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Park MA, Whelan CJ, Ahmed S, Boeringer T, Brown J, Carson TL, Crowder SL, Gage K, Gregg C, Jeong DK, Jim HSL, Judge AR, Mason TM, Parker N, Pillai S, Qayyum A, Rajasekhara S, Rasool G, Tinsley SM, Schabath MB, Stewart P, West J, McDonald P, Permuth JB. Defining and Addressing Research Priorities in Cancer Cachexia through Transdisciplinary Collaboration. Cancers (Basel) 2024; 16:2364. [PMID: 39001427 PMCID: PMC11240731 DOI: 10.3390/cancers16132364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/19/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.
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Affiliation(s)
- Margaret A. Park
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
| | - Christopher J. Whelan
- Department of Metabolism and Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
| | - Sabeen Ahmed
- Department of Machine Learning, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (S.A.); (G.R.)
| | - Tabitha Boeringer
- Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (T.B.); (S.P.)
| | - Joel Brown
- Department of Cancer Biology and Evolution, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (J.B.); (J.W.)
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Tiffany L. Carson
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (T.L.C.); (S.L.C.); (H.S.L.J.); (N.P.); (S.M.T.)
| | - Sylvia L. Crowder
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (T.L.C.); (S.L.C.); (H.S.L.J.); (N.P.); (S.M.T.)
| | - Kenneth Gage
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (K.G.); (D.K.J.); (A.Q.)
| | - Christopher Gregg
- School of Medicine, University of Utah, Salt Lake City, UT 84113, USA;
| | - Daniel K. Jeong
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (K.G.); (D.K.J.); (A.Q.)
| | - Heather S. L. Jim
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (T.L.C.); (S.L.C.); (H.S.L.J.); (N.P.); (S.M.T.)
| | - Andrew R. Judge
- Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA;
| | - Tina M. Mason
- Department of Nursing Research, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
| | - Nathan Parker
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (T.L.C.); (S.L.C.); (H.S.L.J.); (N.P.); (S.M.T.)
| | - Smitha Pillai
- Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (T.B.); (S.P.)
| | - Aliya Qayyum
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (K.G.); (D.K.J.); (A.Q.)
| | - Sahana Rajasekhara
- Department of Supportive Care Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
| | - Ghulam Rasool
- Department of Machine Learning, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (S.A.); (G.R.)
| | - Sara M. Tinsley
- Department of Health Outcomes and Behavior, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (T.L.C.); (S.L.C.); (H.S.L.J.); (N.P.); (S.M.T.)
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Matthew B. Schabath
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
| | - Paul Stewart
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
| | - Jeffrey West
- Department of Cancer Biology and Evolution, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (J.B.); (J.W.)
- Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Patricia McDonald
- Department of Metabolism and Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
- Lexicon Pharmaceuticals, Inc., Woodlands, TX 77381, USA
| | - Jennifer B. Permuth
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA;
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18
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De Lazzari N, Götte M, Kasper S, Meier E, Schuler M, Pogorzelski M, Siveke JT, Tewes M. P-move: a randomized control trial of exercise in patients with advanced pancreatic or biliary tract cancer (aPBC) receiving beyond first-line chemotherapy. Support Care Cancer 2024; 32:437. [PMID: 38879700 PMCID: PMC11180022 DOI: 10.1007/s00520-024-08650-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 06/10/2024] [Indexed: 06/19/2024]
Abstract
PURPOSE Patients with advanced pancreatic and biliary tract cancer (aPBC) frequently suffer from high symptom burden. Exercise can reduce treatment side effects and improve patient-related outcomes (PROMs). However, evidence from prospective studies regarding feasibility and efficacy in advanced settings are sparse. The primary aim of this prospective, randomized-controlled study was to evaluate the feasibility and effects of exercise (ET) in patients with aPBC. METHODS Patients with aPBC beyond first-line therapy were randomized according to the minimization procedure with stratification by gender, age, and loss of body weight in the past six months. The intervention group (IG) completed 3 training units/week for 8 weeks (1x supervised strength sessions, 2x individualized home-based sessions). Control group (CG) received recommendations on physical activity during cancer. RESULTS 41 patients (stage IV pancreatic or biliary tract cancer) were included no adverse events related to exercise occurred during the trial. Physical function increased significantly in IG in 5 out of 7 physical domains. Comparison of IG and CG at 8 weeks (t2) showed significant differences in favour of IG in leg press (p=0.001), bench press (p=0.011), sit-to-stand (p=0.001) and crunch (0.006). Constipation revealed a significant difference in favour of IG at t2 (p=0.033). Quality of life stabilized/increased in IG during the study period compared to a decrease in CG. Throughout/Over the 8 weeks, fatigue notably reduced in the IG (p=0.028). CONCLUSION Exercise is safe and feasible in patients with aPBC undergoing further line therapy. Significant improvements in physical functioning and increased quality of life were achieved. German Clinical Trials Register ID: DRKS00021179; Registration date 15.05.2020.
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Affiliation(s)
- Nico De Lazzari
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147, Essen, Germany
- West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Department of Palliative Medicine, West German Cancer Center, University Hospital Essen, Margot-von-Bonin-Haus, 2. Floor, Room 2.017, Hohlweg 8, 45147, Essen, Germany
| | - Miriam Götte
- West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stefan Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147, Essen, Germany
- German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147, Essen, Germany
- National Center for Tumor Diseases (NCT) West, Campus Essen, University Hospital Essen, 45147, Essen, Germany
| | - Eileen Meier
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147, Essen, Germany
- German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147, Essen, Germany
- National Center for Tumor Diseases (NCT) West, Campus Essen, University Hospital Essen, 45147, Essen, Germany
| | - Michael Pogorzelski
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147, Essen, Germany
| | - Jens T Siveke
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, 45147, Essen, Germany
- Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany
- German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, 45147, Essen, Germany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
- National Center for Tumor Diseases (NCT) West, Campus Essen, University Hospital Essen, 45147, Essen, Germany
| | - Mitra Tewes
- Department of Palliative Medicine, West German Cancer Center, University Hospital Essen, Margot-von-Bonin-Haus, 2. Floor, Room 2.017, Hohlweg 8, 45147, Essen, Germany.
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19
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Mueller TC, Henselmann M, Reischl S, Jaeger C, Trefzer C, Demir IE, Friess H, Martignoni ME. Associations of body composition parameters with postoperative outcome and perineural tumour invasion after oncological pancreatic resection. BMC Surg 2024; 24:175. [PMID: 38835067 DOI: 10.1186/s12893-024-02457-5] [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: 02/01/2024] [Accepted: 05/17/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND Pancreatic cancer is often accompanied by wasting conditions. While surgery is the primary curative approach, it poses a substantial risk of postoperative complications, hindering subsequent treatments. Therefore, identifying patients at high risk for complications and optimizing their perioperative general condition is crucial. Sarcopenia and other body composition abnormalities have shown to adversely affect surgical and oncological outcomes in various cancer patients. As most pancreatic tumours are located close to the neuronal control centre for the digestive tract, it is possible that neural infiltration in this area deranges bowel functions and contributes to malabsorption and malnutrition and ultimately worsen sarcopenia and weight loss. METHODS A retrospective analysis of CT scans was performed for pancreatic cancer patients who underwent surgical tumour resection at a single high-volume centre from 2007 to 2023. Sarcopenia prevalence was assessed by skeletal muscle index (SMI), and visceral obesity was determined by the visceral adipose tissue area (VAT). Obesity and malnutrition were determined by the GLIM criteria. Sarcopenic obesity was defined as simultaneous sarcopenia and obesity. Postoperative complications, mortality and perineural tumour invasion, were compared among patients with body composition abnormalities. RESULTS Of 437 patients studied, 46% were female, the median age was 69 (61;74) years. CT analysis revealed 54.9% of patients with sarcopenia, 23.7% with sarcopenic obesity and 45.9% with visceral obesity. Sarcopenia and sarcopenic obesity were more prevalent in elderly and male patients. Postoperative surgical complications occurred in 67.7% of patients, most of which were mild (41.6%). Severe complications occurred in 22.7% of cases and the mortality rate was 3.4%. Severe postoperative complications were significantly more common in patients with sarcopenia or sarcopenic obesity. Visceral obesity or malnutrition based on BMI alone, did not significantly impact complications. Perineural invasion was found in 80.1% of patients and was unrelated to malnutrition or body composition parameters. CONCLUSIONS This is the first and largest study evaluating the associations of CT-based body mass analysis with surgical outcome and histopathological perineural tumour invasion in pancreatic cancer patients. The results suggest that elderly and male patients are at high risk for sarcopenia and should be routinely evaluated by CT before undergoing pancreatic surgery, irrespective of their BMI. Confirmation of the results in prospective studies is needed to assess if pancreatic cancer patients with radiographic sarcopenia benefit from preoperative amelioration of muscle mass and function by exercise and nutritional interventions.
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Affiliation(s)
- Tara C Mueller
- Department of Surgery, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.
| | - Martin Henselmann
- Department of Surgery, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Stefan Reischl
- Institute of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Carsten Jaeger
- Department of Surgery, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Charlotte Trefzer
- Department of Surgery, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Marc E Martignoni
- Department of Surgery, Klinikum rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
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20
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Sapoor S, Nageh M, Shalma NM, Sharaf R, Haroun N, Salama E, Pratama Umar T, Sharma S, Sayad R. Bidirectional relationship between pancreatic cancer and diabetes mellitus: a comprehensive literature review. Ann Med Surg (Lond) 2024; 86:3522-3529. [PMID: 38846873 PMCID: PMC11152885 DOI: 10.1097/ms9.0000000000002036] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 03/30/2024] [Indexed: 06/09/2024] Open
Abstract
Pancreatic cancer (PC) is a fatal malignant disease. It is well known that the relationship between PC and type 2 diabetes mellitus (T2DM) is a complicated bidirectional relationship. The most important factors causing increased risks of pancreatic cancer are hyperglycaemia, hyperinsulinemia, pancreatitis, and dyslipidemia. Genetics and the immune system also play an important role in the relationship between diabetes mellitus and pancreatic cancer. The primary contributors to this association involve insulin resistance and inflammatory processes within the tumour microenvironment. The combination of diabetes and obesity can contribute to PC by inducing hyperinsulinemia and influencing leptin and adiponectin levels. Given the heightened incidence of pancreatic cancer in diabetes patients compared to the general population, early screening for pancreatic cancer is recommended. Diabetes negatively impacts the survival of pancreatic cancer patients. Among patients receiving chemotherapy, it reduced their survival. The implementation of a healthy lifestyle, including weight management, serves as an initial preventive measure to mitigate the risk of disease development. The role of anti-diabetic drugs on survival is controversial; however, metformin may have a positive impact, especially in the early stages of cancer, while insulin therapy increases the risk of PC.
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Affiliation(s)
| | | | | | - Rana Sharaf
- Faculty of Medicine, Alexandria University, Alexandria
| | - Nooran Haroun
- Faculty of Medicine, Alexandria University, Alexandria
| | - Esraa Salama
- Faculty of Medicine, Alexandria University, Alexandria
| | | | | | - Reem Sayad
- Faculty of Medicine, Assiut University, Assiut, Egypt
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21
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Zhang FM, Zhuang CL, Dong QT, Yu Z, Cheng J, Shen X, Wang SL. Characteristics and prognostic impact of cancer cachexia defined by the Asian Working Group for Cachexia consensus in patients with curable gastric cancer. Clin Nutr 2024; 43:1524-1531. [PMID: 38744096 DOI: 10.1016/j.clnu.2024.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 05/07/2024] [Accepted: 05/08/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND Cachexia is prevalent in cancer patients. The conventional diagnostic criteria for cachexia are often based on Western evidence, lacking consensus for Asian populations. This study aims to compare Asian Working Group for Cachexia (AWGC) criteria with Fearon's criteria, assessing their differences in population characteristics and prognostic impact. METHODS The clinical data of patients who underwent radical gastrectomy between 2013 and 2019 were prospectively collected. Cachexia diagnosis involves the utilization of either AWGC criteria and the previous international consensus proposed by Fearon et al. A scoring model is established based on the optional criteria according to the AWGC criteria. Univariate and multivariate logistic and Cox regression analysis were conducted to determine the independent effect factors for postoperative complications and overall survival. RESULTS In a total of 1330 patients, 461 met AWGC cachexia criteria and 311 met Fearon's criteria. Excluding 262 overlapping cases, those diagnosed solely with AWGC-cachexia had higher age and lower BMI, albumin, hemoglobin, and handgrip strength compared to those by Fearon's criteria alone. AWGC-cachexia independently increased the risk of postoperative complications, whereas Fearon's criteria did not. Patients with AWGC-cachexia also exhibited shorter overall survival than Fearon's criteria. The AWGC-based cachexia grading system effectively stratifies the risks of postoperative complications and mortality. CONCLUSIONS The AWGC criteria is more effective in diagnosing cancer cachexia in the Asian population and provide better prognostic indicators.
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Affiliation(s)
- Feng-Min Zhang
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Cheng-Le Zhuang
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qian-Tong Dong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Zhen Yu
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jun Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xian Shen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
| | - Su-Lin Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
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22
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Turner K, Kim DW, Gonzalez BD, Gore LR, Gurd E, Milano J, Riccardi D, Byrne M, Al-Jumayli M, de Castria TB, Laber DA, Hoffe S, Costello J, Robinson E, Chadha JS, Rajasekhara S, Hume E, Hagen R, Nguyen OT, Nardella N, Parker N, Carson TL, Tabriz AA, Hodul P. Support Through Remote Observation and Nutrition Guidance (STRONG), a digital health intervention to reduce malnutrition among pancreatic cancer patients: A study protocol for a pilot randomized controlled trial. Contemp Clin Trials Commun 2024; 38:101271. [PMID: 38440777 PMCID: PMC10910065 DOI: 10.1016/j.conctc.2024.101271] [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] [Received: 04/20/2023] [Revised: 01/19/2024] [Accepted: 02/13/2024] [Indexed: 03/06/2024] Open
Abstract
Background Malnutrition is a common and distressing condition among pancreatic cancer patients. Fewer than a quarter of pancreatic cancer patients receive medical nutrition therapy (MNT), important for improving nutritional status, weight maintenance, quality of life and survival. System, provider, and patient level barriers limit access to MNT. We propose to examine the feasibility of a 12-week multi-level, digital health intervention designed to expand MNT access among pancreatic cancer patients. Methods Individuals with advanced pancreatic cancer starting chemotherapy (N = 80) will be 1:1 randomized to the intervention or usual care. The Support Through Remote Observation and Nutrition Guidance (STRONG) intervention includes system-level (e.g., routine malnutrition and screening), provider-level (e.g., dietitian training and web-based dashboard), and patient-level strategies (e.g., individualized nutrition plan, self-monitoring of dietary intake via Fitbit, ongoing goal monitoring and feedback). Individuals receiving usual care will be referred to dietitians based on their oncologists' discretion. Study assessments will be completed at baseline, 4-, 8-, 12-, and 16-weeks. Results Primary outcomes will be feasibility (e.g., recruitment, retention, assessment completion) and acceptability. We will collect additional implementation outcomes, such as intervention adherence, perceived usability, and feedback on intervention quality via an exit interview. We will collect preliminary data on outcomes that may be associated with the intervention including malnutrition, quality of life, treatment outcomes, and survival. Conclusion This study will advance our knowledge on the feasibility of a digital health intervention to reduce malnutrition among individuals with advanced pancreatic cancer. Trial registration: NCT05675059, registered on December 9, 2022.
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Affiliation(s)
- Kea Turner
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Dae Won Kim
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Brian D. Gonzalez
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Laurence R. Gore
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, USA
| | - Erin Gurd
- Department of Nutrition Therapy, Moffitt Cancer Center, USA
| | - Jeanine Milano
- Department of Nutrition Therapy, Moffitt Cancer Center, USA
| | - Diane Riccardi
- Department of Nutrition Therapy, Moffitt Cancer Center, USA
| | - Margaret Byrne
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | | | - Tiago Biachi de Castria
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Damian A. Laber
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Sarah Hoffe
- Department of Radiation Oncology, Moffitt Cancer Center, USA
| | - James Costello
- Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, USA
| | - Edmondo Robinson
- Department of Oncological Sciences, University of South Florida, USA
- Department of Internal and Hospital Medicine, Moffitt Cancer Center, USA
- Center for Digital Health, Moffitt Cancer Center, USA
| | | | | | - Emma Hume
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
| | - Ryan Hagen
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
| | - Oliver T. Nguyen
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
| | - Nicole Nardella
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
| | - Nathan Parker
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Tiffany L. Carson
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Amir Alishahi Tabriz
- Department of Health Outcomes and Behavior, Moffitt Cancer Center, USA
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
| | - Pamela Hodul
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, USA
- Department of Oncological Sciences, University of South Florida, USA
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Cao L, Dong M, Jiang K, Zhu Q, Li F, Xiao Z, Tang H, Tao R. Triblock polymer PDMAEMA-co-PNIPAM-co-PMPC to deliver siKRAS for gene therapy in pancreatic cancer. CHEMICAL ENGINEERING JOURNAL 2024; 485:149884. [DOI: 10.1016/j.cej.2024.149884] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
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Alvarez C, Aliru M, Gannavarapu BS, Song T, Gilmore LA, Olaechea S, Ahn C, Infante RE, Iyengar P. Impact of Pretreatment Weight Loss on Radiotherapy Utilization and Clinical Outcomes in Non-Small Cell Lung Cancer. Am J Clin Oncol 2024; 47:49-55. [PMID: 38011024 PMCID: PMC11166469 DOI: 10.1097/coc.0000000000001053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
BACKGROUND Cancer cachexia is a syndrome of unintentional weight loss resulting in progressive functional impairment. Knowledge of radiation therapy utilization in patients with cancer cachexia is limited. We evaluated the use of curative and palliative-intent radiation for the management of patients with non-small cell lung cancer (NSCLC) with cachexia to determine whether tumor-directed therapy affected cachexia-associated outcomes. METHODS Using an Institutional Tumor Registry, we evaluated all patients with stages of NSCLC treated at a tertiary care system from 2006 to 2013. We adopted the international consensus definition for cachexia, with staging designated by the registry and positron emission tomography. Radiotherapy delivery and intent were retrospectively assessed. RESULTS In total, 1330 patients with NSCLC were analyzed. Curative-intent radiotherapy was utilized equally between patients with cachexia and non-cachexia with stages I to III NSCLC. Conversely, significantly more patients with stage IV disease and cachexia received palliative radiotherapy versus those without (74% vs 63%, P = 0.006). Cachexia-associated survival was unchanged irrespective of tumor-directed radiation therapy with curative or palliative intent. In fact, pretreatment cachexia was associated with reduced survival for patients with stage III NSCLC receiving curative-intent radiotherapy (median survival = 23.9 vs 15.0 mo, P = 0.009). Finally, multivariate analysis identified pretreatment cachexia as an independent variable associated with worsened survival (hazard ratio = 1.31, CI: 1.14,1.52). CONCLUSION Patients with advanced NSCLC with cachexia received more palliative-intent radiation than those without weight loss. Tumor-directed therapy in either a curative or palliative approach failed to alter cachexia patient survival across all stages of the disease. These findings offer critical information on the appropriate utilization of radiation in the management of patients with NSCLC with cachexia.
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Affiliation(s)
- Christian Alvarez
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Maureen Aliru
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bhavani S. Gannavarapu
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tidie Song
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Linda Anne Gilmore
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Santiago Olaechea
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Chul Ahn
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Rodney E. Infante
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Puneeth Iyengar
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Riner AN, Herremans KM, Vudatha V, Han S, Qu X, Liu J, Mukhopadhyay N, Freudenberger DC, George TJ, Judge SM, Judge AR, Hughes SJ, Trevino JG. Heterogeneity of weight loss and transcriptomic signatures in pancreatic ductal adenocarcinoma. J Cachexia Sarcopenia Muscle 2024; 15:149-158. [PMID: 38123146 PMCID: PMC10834348 DOI: 10.1002/jcsm.13390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 09/27/2023] [Accepted: 11/02/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is highly associated with cachexia and weight loss, which is driven by the tumour's effect on the body. Data are lacking on differences in these metrics based on PDAC anatomic location. We hypothesize that the primary tumour's anatomic region influences the prevalence and severity of unintentional weight loss. METHODS Treatment naïve patients with PDAC who underwent pancreatectomy at a single institution between 2012 and 2020 were identified retrospectively. Patients with pancreatic head or distal tumours were matched by sex, age, N and T stage. Serologic and anthropometric variables were obtained at the time of diagnosis. Skeletal muscle index (SMI), muscle radiation attenuation (MRA) and adiposity were measured. The primary outcome was presence of significant weight loss [>5% body weight (BW) loss in past 6 months]. Signed rank tests, Cochran Mantel Haenszel tests and Kaplan-Meier survival analysis are presented. RNA-seq of tumours was performed to explore enriched pathways related to cachexia and weight loss. RESULTS Pancreatic head tumours (n = 24) were associated with higher prevalence (70.8% vs. 41.7%, P = 0.081) and degree of weight loss (7.9% vs. 2.5%, P = 0.014) compared to distal tumours (n = 24). BMI (P = 0.642), SMI (P = 0.738) and MRA (P = 0.478) were similar between groups. Combining BW loss, SMI and MRA into a composite score, patients with pancreatic head cancers met more criteria associated with poor prognosis (P = 0.142). Serum albumin (3.9 vs. 4.4 g/dL, P = 0.002) was lower and bilirubin (4.5 vs. 0.4 mg/dL, P < 0.001) were higher with pancreatic head tumours. Survival differed by tumour location (P = 0.014) with numerically higher median overall survival with distal tumours (11.1 vs. 21.8 months; P = 0.066). Transcriptomic analysis revealed inactivation of appetite stimulation, weight regulation and nutrient digestion/metabolism pathways in pancreatic head tumours. CONCLUSIONS Resectable pancreatic head PDAC is associated with higher prevalence of significant weight loss and more poor prognosis features. Pancreaticobiliary obstruction and hypoalbuminemia in patients with head tumours suggests compounding effects of nutrient malabsorption and systemic inflammation on molecular drivers of cachexia, possibly contributing to shorter survival. Therefore, PDAC-associated cachexia is a heterogenous syndrome, which may be influenced by the primary tumour location. Select patients with resectable pancreatic head tumours may benefit from nutritional rehabilitation to improve outcomes.
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Affiliation(s)
- Andrea N. Riner
- Department of SurgeryUniversity of Florida College of MedicineGainesvilleFloridaUSA
| | - Kelly M. Herremans
- Department of SurgeryUniversity of Florida College of MedicineGainesvilleFloridaUSA
| | - Vignesh Vudatha
- Department of SurgeryVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Song Han
- Department of SurgeryUniversity of Florida College of MedicineGainesvilleFloridaUSA
| | - Xufeng Qu
- Department of BiostatisticsVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Jinze Liu
- Department of BiostatisticsVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Nitai Mukhopadhyay
- Department of BiostatisticsVirginia Commonwealth UniversityRichmondVirginiaUSA
| | | | - Thomas J. George
- Department of MedicineUniversity of Florida College of MedicineGainesvilleFloridaUSA
| | - Sarah M. Judge
- Department of Physical TherapyUniversity of Florida Health Science CenterGainesvilleFloridaUSA
| | - Andrew R. Judge
- Department of Physical TherapyUniversity of Florida Health Science CenterGainesvilleFloridaUSA
| | - Steven J. Hughes
- Department of SurgeryUniversity of Florida College of MedicineGainesvilleFloridaUSA
| | - Jose G. Trevino
- Department of SurgeryVirginia Commonwealth UniversityRichmondVirginiaUSA
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Ganju V, Marx G, Pattison S, Amaro-Mugridge NB, Zhao JT, Williams BRG, MacDiarmid JA, Brahmbhatt H. Phase I/IIa Trial in Advanced Pancreatic Ductal Adenocarcinoma Treated with Cytotoxic Drug-Packaged, EGFR-Targeted Nanocells and Glycolipid-Packaged Nanocells. Clin Cancer Res 2024; 30:304-314. [PMID: 37976042 DOI: 10.1158/1078-0432.ccr-23-1821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 09/21/2023] [Accepted: 11/15/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE We assessed the safety and efficacy of an EGFR-targeted, super-cytotoxic drug, PNU-159682-packaged nanocells with α-galactosyl ceramide-packaged nanocells (E-EDV-D682/GC) in patients with advanced pancreatic ductal adenocarcinoma (PDAC) who had exhausted all treatment options. PATIENTS AND METHODS ENG9 was a first-in-man, single-arm, open-label, phase I/IIa, dose-escalation clinical trial. Eligible patients had advanced PDAC, Eastern Cooperative Oncology Group status 0 to 1, and failed all treatments. Primary endpoints were safety and overall survival (OS). RESULTS Of 25 enrolled patients, seven were withdrawn due to rapidly progressive disease and one patient withdrew consent. All 25 patients were assessed for toxicity, 24 patients were assessed for OS, which was also assessed for 17 patients completing one treatment cycle [evaluable subset (ES)]. Nineteen patients (76.0%) experienced at least one treatment-related adverse event (graded 1 to 2) resolving within hours. There were no safety concerns, dose reductions, patient withdrawal, or treatment-related deaths. Median OS (mOS) was 4.4 months; however, mOS of the 17 ES patients was 6.9 months [208 days; range, 83-591 days; 95.0% confidence interval (CI), 5.6-10.3 months] and mOS of seven patients who did not complete one cycle was 1.8 months (54 days; range, 21-72; 95.0% CI, 1.2-2.2 months). Of the ES, 47.1% achieved stable disease and one partial response. Ten subjects in the ES survived over 6 months, the longest 19.7 months. During treatments, 82.0% of the ES maintained stable weight. CONCLUSIONS E-EDV-D682/GC provided significant OS, minimal side effects, and weight stabilization in patients with advanced PDAC. Advanced PDAC can be safely treated with super-cytotoxic drugs via EnGeneIC Dream Vectors to overcome multidrug resistance.
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Affiliation(s)
- Vinod Ganju
- Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University Faculty of Medicine, Nursing and Health Sciences, Clayton, Victoria, Australia
- Peninsula and Southeast Oncology (PASO), Frankston Private Hospital, Frankston, Australia
| | - Gavin Marx
- Sydney Adventist Hospital, Sydney, New South Wales, Australia
| | | | | | | | - Bryan R G Williams
- Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University Faculty of Medicine, Nursing and Health Sciences, Clayton, Victoria, Australia
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Akbar S, Rahman A, Ahmad N, Imran M, Hafeez Z. Understanding the Role of Polyunsaturated Fatty Acids in the Development and Prevention of Cancer. Cancer Treat Res 2024; 191:57-93. [PMID: 39133404 DOI: 10.1007/978-3-031-55622-7_3] [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] [Indexed: 08/13/2024]
Abstract
Polyunsaturated fatty acids (PUFAs), notably omega-3 (n-3) and omega-6 (n-6), have received much attention owing to their multifaceted effects not only in the management of diverse pathological conditions but also in the maintenance of overall health of an individual. A disproportionately high n-6 to n-3 ratio contributes to the development of various disorders including cancer, which ranks as a leading cause of death worldwide with profound social and economic burden. Epidemiological studies and clinical trials combined with the animal and cell culture models have demonstrated the beneficial effects of n-3 PUFAs in reducing the risk of various cancer types including breast, prostate and colon cancer. The anti-cancer actions of n-3 PUFAs are mainly attributed to their role in the modulation of a wide array of cellular processes including membrane dynamics, apoptosis, inflammation, angiogenesis, oxidative stress, gene expression and signal transduction pathways. On the contrary, n-6 PUFAs have been shown to exert pro-tumor actions; however, the inconsistent findings and controversial data emphasize upon the need to further investigation. Nevertheless, one of the biggest challenges in future is to optimize the n-6 to n-3 ratio despite the genetic predisposition, age, gender and disease severity. Moreover, a better understanding of the potential risks and benefits as well as the cellular and molecular mechanisms of the basic actions of these PUFAs is required to explore their role as adjuvants in cancer therapy. All these aspects will be reviewed in this chapter.
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Affiliation(s)
- Samina Akbar
- CALBINOTOX, Université de Lorraine, 54000, Nancy, France.
| | - Abdur Rahman
- Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Nazir Ahmad
- Faculty of Life Sciences, Institute of Home and Food Sciences, Government College University, Faisalabad, Pakistan
| | - Muhammad Imran
- Department of Biosciences, Faculty of Sciences, COMSATS Institute of Information Technology, Park Road, Islamabad, Pakistan
| | - Zeeshan Hafeez
- CALBINOTOX, Université de Lorraine, 54000, Nancy, France
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Yennurajalingam S, Mott F, Lu Z, Urbauer D, Stanton P, Torres H, Rantanen PA, Davis S, Dev R, Hui D, Bruera E. Perception of subjective lived experiences of individuals with anorexia-cachexia in patients with advanced lung cancer. Asia Pac J Oncol Nurs 2023; 10:100314. [PMID: 38197040 PMCID: PMC10772162 DOI: 10.1016/j.apjon.2023.100314] [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] [Received: 05/14/2023] [Accepted: 10/04/2023] [Indexed: 01/11/2024] Open
Abstract
Objective Cancer cachexia (CC) is a frequent and debilitating syndrome in patients with cancer. It has serious implications for patients, extending beyond physical problems into psychological, and social domains. The objective of our study was to qualitatively understand the experiences related to CC in patients with advanced lung cancer. Methods Patients with advanced lung cancer with anorexia (≤ 37 points on Functional Assessment of Anorexia/Cachexia Treatment-ACS) and weight loss were eligible. Patients participated in semi-structured interviews prior to study treatment (n = 19). Qualitative analysis was conducted using interpretative phenomenological approach. Results Two super-ordinate themes emerged (anorexia and weight loss). Patients reported experiencing distress related to anorexia, weight loss, lack of social eating, worsening function, body image, and eating habits. The encouragement to eat by the family was often distressing to the patient. The treatment recommendations by their oncologist for anorexia and weight loss was felt inadequate. Patients felt that the treatment for CC should improve appetite and weight gain as well as their mood and be independent. Conclusions The findings of the study suggests that anorexia and weight loss results in high levels of distress due to their effects on physical and psychosocial domains. Further studies are needed to better understand the experience of anorexia and weight loss to develop strategies to effectively treat CC. Trial registration NCT03637816.
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Affiliation(s)
- Sriram Yennurajalingam
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Frank Mott
- Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Zhanni Lu
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Diana Urbauer
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Penny Stanton
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Hilda Torres
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Petra Ann Rantanen
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Sara Davis
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Rony Dev
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - David Hui
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Eduardo Bruera
- Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
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Guerrier L, Malpuech-Brugère C, Richard R, Touron J. Mitochondrial Function in Healthy Human White Adipose Tissue: A Narrative Review. Nutrients 2023; 15:4430. [PMID: 37892505 PMCID: PMC10609723 DOI: 10.3390/nu15204430] [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: 09/07/2023] [Revised: 10/10/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
As ¾ of the global population either have excess or insufficient fat, it has become increasingly critical to understand the functions and dysfunctions of adipose tissue (AT). AT serves as a key organ in energy metabolism, and recently, attention has been focused on white AT, particularly its mitochondria, as the literature evidence links their functions to adiposity. This narrative review provides an overview of mitochondrial functionality in human white AT. Firstly, it is noteworthy that the two primary AT depots, subcutaneous AT (scAT) and visceral AT (vAT), exhibit differences in mitochondrial density and activity. Notably, vAT tends to have a higher mitochondrial activity compared to scAT. Subsequently, studies have unveiled a negative correlation between mitochondrial activity and body mass index (BMI), indicating that obesity is associated with a lower mitochondrial function. While the impact of exercise on AT mitochondria remains uncertain, dietary interventions have demonstrated varying effects on AT mitochondria. This variability holds promise for the modulation of AT mitochondrial activity. In summary, AT mitochondria exert a significant influence on health outcomes and can be influenced by factors such as obesity and dietary interventions. Understanding the mechanisms underlying these responses can offer potential insights into managing conditions related to AT and overall health.
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Affiliation(s)
- Lisa Guerrier
- Unité de Nutrition Humaine, Université Clermont Auvergne, INRAe, 63000 Clermont-Ferrand, France; (C.M.-B.); (R.R.); (J.T.)
| | - Corinne Malpuech-Brugère
- Unité de Nutrition Humaine, Université Clermont Auvergne, INRAe, 63000 Clermont-Ferrand, France; (C.M.-B.); (R.R.); (J.T.)
- CRNH Auvergne, 63000 Clermont-Ferrand, France
| | - Ruddy Richard
- Unité de Nutrition Humaine, Université Clermont Auvergne, INRAe, 63000 Clermont-Ferrand, France; (C.M.-B.); (R.R.); (J.T.)
- CRNH Auvergne, 63000 Clermont-Ferrand, France
- CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France
| | - Julianne Touron
- Unité de Nutrition Humaine, Université Clermont Auvergne, INRAe, 63000 Clermont-Ferrand, France; (C.M.-B.); (R.R.); (J.T.)
- CRNH Auvergne, 63000 Clermont-Ferrand, France
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Boćkowska M, Kostro P, Kamocki ZK. Phase Angle and Postoperative Complications in a Model of Immunonutrition in Patients with Pancreatic Cancer. Nutrients 2023; 15:4328. [PMID: 37892404 PMCID: PMC10609395 DOI: 10.3390/nu15204328] [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: 09/07/2023] [Revised: 10/08/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND The aim of this study was to determine the influence of our own model of immunonutrition on phase angle and postoperative complications. Our goal was to establish modern prehabilitation procedures for patients operated on for pancreatic cancer. METHODS Patients with pancreatic cancer who qualified for surgical treatment were divided into two groups. Group I (20 patients; 12 with pancreatic head cancer, 8 with pancreatic tail/body cancer) was given immunonutrition (Impact Oral 3× a day, 237 mL, for 5 days before surgery, and after surgery for an average of 3.5 days). Group II (20 patients; 12 with pancreatic head cancer, 8 with pancreatic tail/body cancer) did not receive immunonutrition. Body weight, body mass index and phase angle were assessed on admission to the hospital, after preoperative immunonutrition, on the third and eighth postoperative days. C-reactive protein and Interleukin-1 α were measured on admission to the hospital, after preoperative immunonutrition, on the eighth postoperative day. Postsurgical complications were assessed via Clavien-Dindo classification. RESULTS On admission to the hospital, the phase angle was 5.0° (4.70-5.85) in Group I and 5.1° (5.00-6.25) in Group II. After 5 days of using preoperative immunonutrition, it increased statistically significantly (p < 0.02) to 5.35°. In Group I, on the third day after surgery, it decreased statistically significantly (p < 0.001) to 4.65°, and then, increased to 4.85° on the eighth day. In Group II, statistically significant decreases in the phase angle were observed on the third (4.5°; p < 0.002) and eighth (4.55°; p < 0.008) days after surgery. A statistically significant increase in CRP (86.6 mg/dL; p < 0.02) and IL-1α (18.5 pg/mL; p < 0.03) levels was observed on the eighth day after surgery in this group. In Group I, a statistically significant negative correlation (R -0.501106; p < 0.002) of the phase angle after 5 days of preoperative immunonutrition with postoperative complications was observed. CONCLUSIONS This study used our own model of immunonutrition in patients undergoing surgery for pancreatic cancer. The applied model of perioperative IN improved the postoperative course of patients operated on due to pancreatic cancer. Fewer complications were observed in patients in the group receiving IN. Also, the PA value increased after the 5-day preoperative IN, and the use of perioperative IN improved the PA value on the eighth postoperative day compared to the group that did not receive IN. On this day, an increase in inflammatory parameters was also observed in the group that did not receive IN. In addition, PA correlated negatively with complications. The PA can be a useful tool to assess the effectiveness of the applied IN, and thus, to predict the occurrence of postoperative complications. Therefore, there is a further need for studies on larger groups of patients.
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Affiliation(s)
- Magdalena Boćkowska
- Second Department of General and Gastroenterological Surgery, Medical University of Bialystok, M. Sklodowskiej-Curie Street 24a, 15-276 Bialystok, Poland
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Mandl J, Baumer S, Holtzem B, Theurer R, Zorger N, Pech O. [Sarcopenia in patients with pancreatic cancer, an independant prognostic factor]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:1365-1370. [PMID: 36482058 DOI: 10.1055/a-1959-2894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Pancreatic cancer is despite modern diagnostic tools and treatment regimen associated with poor outcome. Many patients show cachexia and sarcopenia. METHODS In a retrospective analysis the SMI (cm²/m²) was measured by determining the skelettal muscle area in a computed tomography image at lumbar vertebrae 3. Further clinical parameters were measured to determine the outcome. RESULTS The mean survival after diagnosis in the population with sarcopenia was significantly lower (14,4 vs 17,7 months, p=0,046). Significantly shorter survival was also seen for higher age (p=0,006), no tumor resection (p=0,004), metastases (p=0,002) and high CA19-9 level (p=0,002) CONCLUSION: Sarcopenia is an indipendant prognostic factor in patients with pancreatic cancer. SMI should be measured clinical practice and further studies are necessary to asses a potential therapeutic strategy.
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Affiliation(s)
- Johanna Mandl
- Klinik für Gastroenterologie und interventionelle Endoskopie, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
| | - Sebastian Baumer
- Klinik für Gastroenterologie und interventionelle Endoskopie, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
| | - Bernadette Holtzem
- Klinik für Gastroenterologie und interventionelle Endoskopie, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
| | - Rainer Theurer
- Institut für Radiologie, Neuroradiologie und Nuklearmedizin, Krankenhaus Barmherzige Bruder Regensburg, Regensburg, Germany
| | - Niels Zorger
- Institut für Radiologie, Neuroradiologie und Nuklearmedizin, Krankenhaus Barmherzige Bruder Regensburg, Regensburg, Germany
| | - Oliver Pech
- Klinik für Gastroenterologie und interventionelle Endoskopie, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
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Brown M, O'Connor D, Turkington R, Eatock M, Vince R, Hulme C, Bowdery R, Robinson R, Wadsley J, Maraveyas A, Prue G. Feasibility of delivering supervised exercise training following surgical resection and during adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PRECISE): a case series. BMC Sports Sci Med Rehabil 2023; 15:116. [PMID: 37735664 PMCID: PMC10514993 DOI: 10.1186/s13102-023-00722-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 09/05/2023] [Indexed: 09/23/2023]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm, with surgical resection and adjuvant chemotherapy the only curative treatment. Treatment-related toxicities place a considerable burden on patients although exercise training has shown promise is helping to manage such adversities and facilitate rehabilitation. The feasibility and safety of exercise training as a supportive therapy during adjuvant chemotherapy remains unknown. METHODS Patients with PDAC were screened post-surgical resection and enrolled in a 16-week, progressive, concurrent exercise programme alongside their chemotherapy regimen. Feasibility was the primary objective detailing recruitment, retention and adherence rates throughout as well as the safety and fidelity of the intervention. Secondarily, the impact on functional fitness and patient-reported outcomes was captured at baseline, post-intervention and 3-month follow up. RESULTS Eight patients consented to participate in this trial, with five proceeding to enrol in exercise training. Concurrent exercise training is feasible and safe during adjuvant chemotherapy and prevented an expected decline in functional fitness and patient-reported outcomes during this time. DISCUSSION This case series provides preliminary evidence that concurrent exercise training during adjuvant therapy is safe, feasible and well tolerated, preventing an expected decline in functional fitness, muscular strength and health-related quality of life (HRQoL). Given the adverse effects of treatment, these findings are promising and provide further evidence for the inclusion of exercise training as a standard of care for surgical rehabilitation and managing treatment-related toxicities. Future research should explore the impact of exercise training during neoadjuvant chemotherapy, with prehabilitation now standard practice for borderline resectable disease. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04305067, prospectively registered 12/03/2020, https://classic. CLINICALTRIALS gov/ct2/show/NCT04305067 .
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Affiliation(s)
- Malcolm Brown
- School of Nursing and Midwifery, Queen's University Belfast Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK.
| | - Dominic O'Connor
- School of Health Sciences, The University of Nottingham, Nottingham, England, UK
| | - Richard Turkington
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, UK
- The Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Martin Eatock
- The Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, UK
- The Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Rebecca Vince
- School of Sport, Exercise and Rehabilitation Sciences, University of Hull, Hull, England, UK
| | - Claire Hulme
- Department of Health and Community Sciences, University of Exeter Medical School, Exeter, England, UK
| | - Roy Bowdery
- Pancreatic Cancer UK Research Involvement Network, London, England, UK
| | - Rebecca Robinson
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England, UK
| | - Jonathan Wadsley
- Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, England, UK
| | | | - Gillian Prue
- School of Nursing and Midwifery, Queen's University Belfast Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK
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Cefalì M, Scala I, Pavone G, Helbling D, Hussung S, Fritsch R, Reiner C, Stocker S, Koeberle D, Kissling M, Chianca V, Del Grande F, De Dosso S, Rizzo S. Is Computed-Tomography-Based Body Composition a Reliable Predictor of Chemotherapy-Related Toxicity in Pancreatic Cancer Patients? Cancers (Basel) 2023; 15:4398. [PMID: 37686674 PMCID: PMC10486498 DOI: 10.3390/cancers15174398] [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: 04/14/2023] [Revised: 08/13/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023] Open
Abstract
BACKGROUND Malnutrition, loss of weight and of skeletal muscle mass are frequent in pancreatic cancer patients, a majority of which will undergo chemotherapy over the course of their disease. Available data suggest a negative prognostic role of these changes in body composition on disease outcomes; however, it is unclear whether tolerance to chemotherapeutic treatment is similarly and/or negatively affected. We aimed to explore this association by retrospectively assessing changes in body composition and chemotherapy-related toxicity in a cohort of advanced pancreatic cancer patients. METHODS Body composition was evaluated through clinical parameters and through radiological assessment of muscle mass, skeletal muscle area, skeletal muscle index and skeletal muscle density; and an assessment of fat distribution by subcutaneous adipose tissue and visceral adipose tissue. We performed descriptive statistics, pre/post chemotherapy comparisons and uni- and multivariate analyses to assess the relation between changes in body composition and toxicity. RESULTS Toxicity risk increased with an increase of skeletal muscle index (OR: 1.03) and body mass index (OR: 1.07), whereas it decreased with an increase in skeletal muscle density (OR: 0.96). Multivariate analyses confirmed a reduction in the risk of toxicity only with an increase in skeletal muscle density (OR: 0.96). CONCLUSIONS This study suggests that the retrospective analysis of changes in body composition is unlikely to be useful to predict toxicity to gemcitabine-nab-paclitaxel.
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Affiliation(s)
- Marco Cefalì
- Istituto Oncologico della Svizzera Italiana (IOSI), Ente Ospedaliero Cantonale (EOC), 6500 Bellinzona, Switzerland; (M.C.); (G.P.)
| | - Isabel Scala
- Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Via Buffi 13, 6900 Lugano, Switzerland; (I.S.); (F.D.G.); (S.R.)
| | - Giuliana Pavone
- Istituto Oncologico della Svizzera Italiana (IOSI), Ente Ospedaliero Cantonale (EOC), 6500 Bellinzona, Switzerland; (M.C.); (G.P.)
| | - Daniel Helbling
- Onkozentrum Zürich, Seestrasse 259, 8038 Zurich, Switzerland;
| | - Saskia Hussung
- Department of Medical Oncology and Hematology, University Hospital of Zurich, 8091 Zurich, Switzerland; (S.H.); (R.F.)
| | - Ralph Fritsch
- Department of Medical Oncology and Hematology, University Hospital of Zurich, 8091 Zurich, Switzerland; (S.H.); (R.F.)
| | - Cäcilia Reiner
- Institute for Diagnostic and Interventional Radiology, University Hospital of Zurich, 8091 Zurich, Switzerland; (C.R.); (S.S.)
| | - Soleen Stocker
- Institute for Diagnostic and Interventional Radiology, University Hospital of Zurich, 8091 Zurich, Switzerland; (C.R.); (S.S.)
| | - Dieter Koeberle
- Oncology Departement, St. Claraspital, Kleinriehenstrasse 39, 4058 Basel, Switzerland;
| | - Marc Kissling
- Radiology Department, St. Claraspital, Kleinriehenstrasse 39, 4058 Basel, Switzerland;
| | - Vito Chianca
- Istituto di Imaging della Svizzera Italiana (IIMSI), Ente Ospedaliero Cantonale (EOC), Via Tesserete 46, 6900 Lugano, Switzerland;
| | - Filippo Del Grande
- Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Via Buffi 13, 6900 Lugano, Switzerland; (I.S.); (F.D.G.); (S.R.)
- Istituto di Imaging della Svizzera Italiana (IIMSI), Ente Ospedaliero Cantonale (EOC), Via Tesserete 46, 6900 Lugano, Switzerland;
| | - Sara De Dosso
- Istituto Oncologico della Svizzera Italiana (IOSI), Ente Ospedaliero Cantonale (EOC), 6500 Bellinzona, Switzerland; (M.C.); (G.P.)
- Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Via Buffi 13, 6900 Lugano, Switzerland; (I.S.); (F.D.G.); (S.R.)
| | - Stefania Rizzo
- Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Via Buffi 13, 6900 Lugano, Switzerland; (I.S.); (F.D.G.); (S.R.)
- Istituto di Imaging della Svizzera Italiana (IIMSI), Ente Ospedaliero Cantonale (EOC), Via Tesserete 46, 6900 Lugano, Switzerland;
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Yamada M, Warabi E, Oishi H, Lira VA, Okutsu M. Muscle p62 stimulates the expression of antioxidant proteins alleviating cancer cachexia. FASEB J 2023; 37:e23156. [PMID: 37624620 PMCID: PMC10560086 DOI: 10.1096/fj.202300349r] [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: 04/10/2023] [Revised: 07/26/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023]
Abstract
Oxidative stress plays an important role in skeletal muscle atrophy during cancer cachexia, and more glycolytic muscles are preferentially affected. Sequestosome1/SQSTM1 (i.e., p62), particularly when phosphorylated at Ser 349 (Ser 351 in mice), competitively binds to the Kelch-like ECH-associated protein 1 (Keap1) activating Nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 then stimulates the transcription of antioxidant/electrophile-responsive elements in target genes. However, a potential role for p62 in the protection of muscle wasting in cachexia remains to be determined. Here, using the well-established cachexia-inducing model of Lewis Lung Carcinoma (LLC) in mice we demonstrate higher expression of antioxidant proteins (i.e., NQO1, HO-1, GSTM1, CuZnSOD, MnSOD, and EcSOD) in the more oxidative and cachexia resistant soleus muscle than in the more glycolytic and cachexia prone extensor digitorum longus muscle. This was accompanied by higher p62 (total and phosphorylated) and nuclear Nrf2 levels in the soleus, which were paralleled by higher expression of proteins known to either phosphorylate or promote p62 phosphorylation (i.e., NBR1, CK1, PKCδ, and TAK1). Muscle-specific p62 gain-of-function (i.e., in p62 mTg mice) activated Nrf2 nuclear translocation and increased the expression of multiple antioxidant proteins (i.e., CuZnSOD, MnSOD, EcSOD, NQO1, and GSTM1) in glycolytic muscles. Interestingly, skeletal muscle Nrf2 haplodeficiency blunted the increases of most of these proteins (i.e., CuZnSOD, EcSOD, and NQO1) suggesting that muscle p62 stimulates antioxidant protein expression also via additional, yet to be determined mechanisms. Of note, p62 gain-of-function mitigated glycolytic muscle wasting in LLC-affected mice. Collectively, our findings identify skeletal muscle p62 as a potential therapeutic target for cancer cachexia.
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Affiliation(s)
- Mami Yamada
- Graduate School of Science, Nagoya City University, Nagoya, Japan
| | - Eiji Warabi
- Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hisashi Oishi
- Department of Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Vitor A. Lira
- Department of Health and Human Physiology, Obesity Research and Education Initiative, F.O.E. Diabetes Research Center, Abboud Cardiovascular Research Center, Pappajohn Biomedical Institute, The University of Iowa, IA, USA
| | - Mitsuharu Okutsu
- Graduate School of Science, Nagoya City University, Nagoya, Japan
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Klassen PN, Baracos V, Ghosh S, Martin L, Sawyer MB, Mazurak VC. Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer. Cancers (Basel) 2023; 15:4368. [PMID: 37686641 PMCID: PMC10486774 DOI: 10.3390/cancers15174368] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/21/2023] [Accepted: 08/29/2023] [Indexed: 09/10/2023] Open
Abstract
Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013-2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm2/m2) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox's proportional hazards models. Tissue changes varied widely (∆SMI: -17.8 to +7.3 cm2/m2, ∆ATI: -106.1 to +37.7 cm2/m2) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (-3.2 cm2/m2, p < 0.001; -12.4 cm2/m2, p = 0.001). FOLFIRINOX was associated with greater muscle loss (-1.6 cm2/m2, p = 0.013) and GEM/NAB with greater adipose loss (-11.2 cm2/m2, p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies.
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Affiliation(s)
- Pamela N. Klassen
- Department of Agricultural, Food & Nutritional Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Vickie Baracos
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Sunita Ghosh
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Lisa Martin
- Nutrition Services, Alberta Health Services, Edmonton, AB T5J 3E4, Canada
| | - Michael B. Sawyer
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Vera C. Mazurak
- Department of Agricultural, Food & Nutritional Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada
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Zhang K, Chen Y, Zhu J, Ge X, Wu J, Xu P, Yao J. Advancement of single-cell sequencing for clinical diagnosis and treatment of pancreatic cancer. Front Med (Lausanne) 2023; 10:1213136. [PMID: 37720505 PMCID: PMC10501729 DOI: 10.3389/fmed.2023.1213136] [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: 04/27/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
Single-cell sequencing is a high-throughput technique that enables detection of genomic, transcriptomic, and epigenomic information at the individual cell level, offering significant advantages in detecting cellular heterogeneity, precise cell classification, and identifying rare subpopulations. The technique holds tremendous potential in improving the diagnosis and treatment of pancreatic cancer. Moreover, single-cell sequencing provides unique insights into the mechanisms of pancreatic cancer metastasis and cachexia, paving the way for developing novel preventive strategies. Overall, single-cell sequencing has immense potential in promoting early diagnosis, guiding personalized treatment, and preventing complications of pancreatic cancer. Emerging single-cell sequencing technologies will undoubtedly enhance our understanding of the complex biology of pancreatic cancer and pave the way for new directions in its clinical diagnosis and treatment.
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Affiliation(s)
- Ke Zhang
- Dalian Medical University, Dalian, China
| | - Yuan Chen
- Medical College of Yangzhou University, Yangzhou, China
| | - Jie Zhu
- Medical College of Yangzhou University, Yangzhou, China
| | - Xinyu Ge
- Dalian Medical University, Dalian, China
| | - Junqing Wu
- Medical College of Yangzhou University, Yangzhou, China
| | - Peng Xu
- Northern Jiangsu People’s Hospital Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Jie Yao
- Northern Jiangsu People’s Hospital Clinical Medical College, Yangzhou University, Yangzhou, China
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Vedire Y, Nitsche L, Tiadjeri M, McCutcheon V, Hall J, Barbi J, Yendamuri S, Ray AD. Skeletal muscle index is associated with long term outcomes after lobectomy for non-small cell lung cancer. BMC Cancer 2023; 23:778. [PMID: 37598139 PMCID: PMC10439565 DOI: 10.1186/s12885-023-11210-9] [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: 11/22/2022] [Accepted: 07/23/2023] [Indexed: 08/21/2023] Open
Abstract
BACKGROUND Skeletal muscle indices have been associated with improved peri-operative outcomes after surgical resection of non-small-cell lung cancer (NSCLC). However, it is unclear if these indices can predict long term cancer specific outcomes. METHODS NSCLC patients undergoing lobectomy at our institute between 2009-2015 were included in this analysis (N = 492). Preoperative CT scans were used to quantify skeletal muscle index (SMI) at L4 using sliceOmatic software. Cox proportional modelling was performed for overall (OS) and recurrence free survival (RFS). RESULTS For all patients, median SMI was 45.7 cm2/m2 (IQR, 40-53.8). SMI was negatively associated with age (R = -0.2; p < 0.05) and positively associated with BMI (R = 0.46; P < 0.05). No association with either OS or RFS was seen with univariate cox modelling. However, multivariable modelling for SMI with patient age, gender, race, smoking status, DLCO and FEV1 (% predicted), American Society of Anesthesiology (ASA) score, tumor histology and stage, and postoperative neoadjuvant therapy showed improved OS (HR = 0.97; P = 0.0005) and RFS (HR = 0.97; P = 0.01) with SMI. Using sex specific median SMI as cutoff, a lower SMI was associated with poor OS (HR = 1.65, P = 0.001) and RFS (HR = 1.47, P = 0.03). CONCLUSIONS SMI is associated with improved outcomes after resection of NSCLC. Further studies are needed to understand the biological basis of this observation. This study provides additional rationale for designing and implementation of rehabilitation trials after surgical resection, to gain durable oncologic benefit.
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Affiliation(s)
- Yeshwanth Vedire
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Lindsay Nitsche
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Madeline Tiadjeri
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Victor McCutcheon
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Jack Hall
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
- Department of Physical Therapy and Rehabilitation, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Joseph Barbi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, Ny, 14263, USA
| | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
| | - Andrew D Ray
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
- Department of Rehabilitation, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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van der Kroft G, Wee L, Rensen SS, Brecheisen R, van Dijk DPJ, Eickhoff R, Roeth AA, Ulmer FT, Dekker A, Neumann UP, Olde Damink SWM. Identifying radiomics signatures in body composition imaging for the prediction of outcome following pancreatic cancer resection. Front Oncol 2023; 13:1062937. [PMID: 37637046 PMCID: PMC10449585 DOI: 10.3389/fonc.2023.1062937] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 06/26/2023] [Indexed: 08/29/2023] Open
Abstract
Background Computerized radiological image analysis (radiomics) enables the investigation of image-derived phenotypes by extracting large numbers of quantitative features. We hypothesized that radiomics features may contain prognostic information that enhances conventional body composition analysis. We aimed to investigate whether body composition-associated radiomics features hold additional value over conventional body composition analysis and clinical patient characteristics used to predict survival of pancreatic ductal adenocarcinoma (PDAC) patients. Methods Computed tomography images of 304 patients undergoing elective pancreatic cancer resection were analysed. 2D radiomics features were extracted from skeletal muscle and subcutaneous and visceral adipose tissue (SAT and VAT) compartments from a single slice at the third lumbar vertebra. The study population was randomly split (80:20) into training and holdout subsets. Feature ranking with Least Absolute Shrinkage Selection Operator (LASSO) followed by multivariable stepwise Cox regression in 1000 bootstrapped re-samples of the training data was performed and tested on the holdout data. The fitted regression predictors were used as "scores" for a clinical (C-Score), body composition (B-Score), and radiomics (R-Score) model. To stratify patients into the highest 25% and lowest 25% risk of mortality compared to the middle 50%, the Harrell Concordance Index was used. Results Based on LASSO and stepwise cox regression for overall survival, ASA ≥3 and age were the most important clinical variables and constituted the C-score, and VAT-index (VATI) was the most important body composition variable and constituted the B-score. Three radiomics features (SATI_original_shape2D_Perimeter, VATI_original_glszm_SmallAreaEmphasis, and VATI_original_firstorder_Maximum) emerged as the most frequent set of features and yielded an R-Score. Of the mean concordance indices of C-, B-, and R-scores, R-score performed best (0.61, 95% CI 0.56-0.65, p<0.001), followed by the C-score (0.59, 95% CI 0.55-0.63, p<0.001) and B-score (0.55, 95% CI 0.50-0.60, p=0.03). Kaplan-Meier projection revealed that C-, B, and R-scores showed a clear split in the survival curves in the training set, although none remained significant in the holdout set. Conclusion It is feasible to implement a data-driven radiomics approach to body composition imaging. Radiomics features provided improved predictive performance compared to conventional body composition variables for the prediction of overall survival of PDAC patients undergoing primary resection.
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Affiliation(s)
- Gregory van der Kroft
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, European Surgical Center Aachen Maastricht (ESCAM), Aachen, Germany
| | - Leonard Wee
- Department of Radiation Oncology (MAASTRO), GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Sander S. Rensen
- Department of Surgery, Maastricht University Medical Center, European Surgical Center Aachen Maastricht (ESCAM), Maastricht, Netherlands
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Ralph Brecheisen
- Department of Surgery, Maastricht University Medical Center, European Surgical Center Aachen Maastricht (ESCAM), Maastricht, Netherlands
| | - David P. J. van Dijk
- Department of Surgery, Maastricht University Medical Center, European Surgical Center Aachen Maastricht (ESCAM), Maastricht, Netherlands
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Roman Eickhoff
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, European Surgical Center Aachen Maastricht (ESCAM), Aachen, Germany
| | - Anjali A. Roeth
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, European Surgical Center Aachen Maastricht (ESCAM), Aachen, Germany
| | - Florian T. Ulmer
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, European Surgical Center Aachen Maastricht (ESCAM), Aachen, Germany
| | - Andre Dekker
- Department of Radiation Oncology (MAASTRO), GROW, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Ulf P. Neumann
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, European Surgical Center Aachen Maastricht (ESCAM), Aachen, Germany
- Department of Surgery, Maastricht University Medical Center, European Surgical Center Aachen Maastricht (ESCAM), Maastricht, Netherlands
| | - Steven W. M. Olde Damink
- Department of General, Gastrointestinal, Hepatobiliary and Transplant Surgery, RWTH Aachen University Hospital, European Surgical Center Aachen Maastricht (ESCAM), Aachen, Germany
- Department of Surgery, Maastricht University Medical Center, European Surgical Center Aachen Maastricht (ESCAM), Maastricht, Netherlands
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
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Mękal D, Sobocki J, Badowska-Kozakiewicz A, Sygit K, Cipora E, Bandurska E, Czerw A, Deptała A. Evaluation of Nutritional Status and the Impact of Nutritional Treatment in Patients with Pancreatic Cancer. Cancers (Basel) 2023; 15:3816. [PMID: 37568634 PMCID: PMC10417457 DOI: 10.3390/cancers15153816] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/17/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Patients with pancreatic cancer who develop irreversible cancer cachexia have a life expectancy of less than 3 months. Therefore, it is extremely important to evaluate the patient's nutritional status as early as possible and to implement an appropriate nutritional intervention in order to reduce the risk of further weight loss and/or muscle loss, which affect the outcomes of cancer treatment and the correct nutritional treatment in patients with pancreatic cancer. A literature review was performed by using the PubMed and Cochrane quick search methodology. The main purpose of this review was to present the current approach to nutritional treatment in pancreatic cancer. The review included publications, most of which concerned clinical nutrition as part of the phase of treatment of patients with pancreatic cancer, nutritional and metabolic disorders in pancreatic cancer, and the period after pancreatic resection. Some of the publications concerned various nutritional interventions in patients with pancreatic cancer undergoing chemotherapy or surgical treatment (nutritional support before surgery, after surgery, or during palliative treatment). There is an unmet need for integrated nutritional therapy as a key part of the comprehensive care process for PC patients. Nutritional counseling is the first line of nutritional treatment for malnourished cancer patients, but pancreatic enzyme replacement therapy also constitutes the cornerstone of nutritional treatment for relieving symptoms of indigestion and maintaining or improving nutritional status.
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Affiliation(s)
- Dominika Mękal
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.B.-K.); (A.D.)
| | - Jacek Sobocki
- Department of General Surgery and Clinical Nutrition, Centre for Postgraduate Medical Education, 01-813 Warsaw, Poland;
| | - Anna Badowska-Kozakiewicz
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (A.B.-K.); (A.D.)
| | - Katarzyna Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland;
| | - Elżbieta Cipora
- Medical Institute, Jan Grodek State University, 38-500 Sanok, Poland;
| | - Ewa Bandurska
- Center for Competence Development, Integrated Care and e-Health, Medical University of Gdansk, 80-204 Gdansk, 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; (A.B.-K.); (A.D.)
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Sandini M, Paiella S, Cereda M, Angrisani M, Capretti G, Famularo S, Giani A, Roccamatisi L, Fontani A, Malleo G, Salvia R, Roviello F, Zerbi A, Bassi C, Gianotti L. Independent effect of fat-to-muscle mass ratio at bioimpedance analysis on long-term survival in patients receiving surgery for pancreatic cancer. Front Nutr 2023; 10:1118616. [PMID: 37384108 PMCID: PMC10298166 DOI: 10.3389/fnut.2023.1118616] [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: 12/07/2022] [Accepted: 05/05/2023] [Indexed: 06/30/2023] Open
Abstract
INTRODUCTION Malnutrition and alteration of body composition are early features in pancreatic cancer and appear to be predictors of advanced stages and dismal overall survival. Whether specific patient characteristics measured at the preoperative bioimpedance analysis (BIA) could be associated with long-term outcomes following curative resection has not been yet described. METHODS In a prospective multicenter study, all histologically proven resected pancreatic cancer patients were included in the analysis. BIA was measured for all patients on the day before surgery. Demographics, perioperative data, and postoperative outcomes were prospectively collected. Patients who experienced 90-day mortality were excluded from the analysis. Survival data were obtained through follow-up visits and phone interviews. Bioimpedance variables were analyzed according to the overall survival using the Kaplan-Meier curves and the univariate and multivariate Cox regression model. RESULTS Overall, 161 pancreatic cancer patients were included. The median age was 66 (60-74) years, and 27.3% received systemic neoadjuvant treatment. There were 23 (14.3%) patients malnourished in the preoperative evaluation. Median OS was 34.0 (25.7-42.3) months. Several bioimpedance variables were associated with OS at the univariate analysis, namely the phase angle [HR 0.85, 95% CI 0.74-0.98)], standardized phase angle [HR 0.91, 95% CI 0.82-0.99)], and an increased ratio between the fat and lean mass (FM/FFM) [HR 4.27, 95% CI 1.10-16.64)]. At the multivariate analysis, the FM/FFM ratio was a confirmed independent predictor of OS following radical resection, together with a positive lymph nodal status. CONCLUSION Alteration of body composition at the preoperative bioimpedance vector analysis (BIVA) can predict dismal oncologic outcomes following pancreatic resection for cancer.
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Affiliation(s)
- Marta Sandini
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Salvatore Paiella
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Marco Cereda
- Department of Surgery, San Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Marco Angrisani
- Department of General, Hepatobiliary and Pancreatic Surgery, Liver Transplantation Service, San Camillo Forlanini Hospital, Rome, Italy
| | - Giovanni Capretti
- Pancreatic Surgery Unit, Department of Biomedical Sciences, Humanitas Clinical and Research Center-IRCCS Rozzano, Humanitas University, Milan, Italy
| | - Simone Famularo
- Pancreatic Surgery Unit, Department of Biomedical Sciences, Humanitas Clinical and Research Center-IRCCS Rozzano, Humanitas University, Milan, Italy
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, Milan, Italy
| | - Alessandro Giani
- Department of Surgery, San Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Linda Roccamatisi
- Department of Surgery, San Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Andrea Fontani
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Giuseppe Malleo
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Franco Roviello
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Alessandro Zerbi
- Pancreatic Surgery Unit, Department of Biomedical Sciences, Humanitas Clinical and Research Center-IRCCS Rozzano, Humanitas University, Milan, Italy
| | - Claudio Bassi
- General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Luca Gianotti
- Department of Surgery, San Gerardo Hospital, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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Liao WC, Chen CT, Tsai YS, Wang XY, Chang YT, Wu MS, Chow LP. S100A8, S100A9 and S100A8/A9 heterodimer as novel cachexigenic factors for pancreatic cancer-induced cachexia. BMC Cancer 2023; 23:513. [PMID: 37280516 DOI: 10.1186/s12885-023-11009-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 05/25/2023] [Indexed: 06/08/2023] Open
Abstract
BACKGROUND Cancer cachexia, occurring in ~ 80% pancreatic cancer (PC) patients overall, is a paraneoplastic syndrome mediated by cancer-induced systemic inflammation and characterized by weight loss and skeletal muscle wasting. Identifying clinically relevant PC-derived pro-inflammatory factors with cachexigenic potential may provide novel insights and therapeutic strategies. METHODS Pro-inflammatory factors with cachexigenic potential in PC were identified by bioinformatic analysis. The abilities of selected candidate factors in inducing skeletal muscle atrophy were investigated. Expression levels of candidate factors in tumors and sera was compared between PC patients with and without cachexia. Associations between serum levels of the candidates and weight loss were assessed in PC patients. RESULTS S100A8, S100A9, and S100A8/A9 were identified and shown to induce C2C12 myotube atrophy. Tumors of PC patients with cachexia had markedly elevated expression of S100A8 (P = 0.003) and S100A9 (P < 0.001). PC patients with cachexia had significantly higher serum levels of S100A8, S100A9 and S100A8/A9. Serum levels of these factors positively correlated with percentage of weight loss [correlation coefficient: S100A8: 0.33 (P < 0.001); S100A9: 0.30 (P < 0.001); S100A8/A9: 0.24 (P = 0.004)] and independently predicted the occurrence of cachexia [adjusted odds ratio (95% confidence interval) per 1ng/ml increase: S100A8 1.11 (1.02-1.21), P = 0.014; S100A9 1.10 (1.04-1.16), P = 0.001; per 1 µg/ml increase: S100A8/A9 1.04 (1.01-1.06), P = 0.009]. CONCLUSIONS Atrophic effects of S100A8, S100A9, and S100A8/A9 indicated them as potential pathogenic factors of PC-induced cachexia. In addition, the correlation with the degree of weight loss and prediction of cachexia in PC patients implicated their potential utility in the diagnosis of PC-induced cachexia.
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Affiliation(s)
- Wei-Chih Liao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chih-Ta Chen
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No.1, Jen-Ai Road Section 1, Taipei, 10051, Taiwan
| | - You-Shu Tsai
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No.1, Jen-Ai Road Section 1, Taipei, 10051, Taiwan
| | - Xin-Ya Wang
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No.1, Jen-Ai Road Section 1, Taipei, 10051, Taiwan
| | - Yen-Tzu Chang
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No.1, Jen-Ai Road Section 1, Taipei, 10051, Taiwan
| | - Ming-Shiang Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Lu-Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No.1, Jen-Ai Road Section 1, Taipei, 10051, Taiwan.
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Neyroud D, Laitano O, Dasgupta A, Lopez C, Schmitt RE, Schneider JZ, Hammers DW, Sweeney HL, Walter GA, Doles J, Judge SM, Judge AR. Blocking muscle wasting via deletion of the muscle-specific E3 ligase MuRF1 impedes pancreatic tumor growth. Commun Biol 2023; 6:519. [PMID: 37179425 PMCID: PMC10183033 DOI: 10.1038/s42003-023-04902-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigate the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induces progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grow slower, and show an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 is necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.
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Affiliation(s)
- Daria Neyroud
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA
- Myology Institute, University of Florida, Gainesville, FL, USA
- Institute of Sports Sciences, University of Lausanne, Lausanne, Switzerland
| | - Orlando Laitano
- Myology Institute, University of Florida, Gainesville, FL, USA
- Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, USA
| | - Aneesha Dasgupta
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Christopher Lopez
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA
- Myology Institute, University of Florida, Gainesville, FL, USA
| | - Rebecca E Schmitt
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Jessica Z Schneider
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - David W Hammers
- Myology Institute, University of Florida, Gainesville, FL, USA
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - H Lee Sweeney
- Myology Institute, University of Florida, Gainesville, FL, USA
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Glenn A Walter
- Myology Institute, University of Florida, Gainesville, FL, USA
- Department of Physiology and Aging, University of Florida, Gainesville, FL, USA
| | - Jason Doles
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Sarah M Judge
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA
- Myology Institute, University of Florida, Gainesville, FL, USA
| | - Andrew R Judge
- Department of Physical Therapy, University of Florida, Gainesville, FL, USA.
- Myology Institute, University of Florida, Gainesville, FL, USA.
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Ferrer M, Anthony TG, Ayres JS, Biffi G, Brown JC, Caan BJ, Cespedes Feliciano EM, Coll AP, Dunne RF, Goncalves MD, Grethlein J, Heymsfield SB, Hui S, Jamal-Hanjani M, Lam JM, Lewis DY, McCandlish D, Mustian KM, O'Rahilly S, Perrimon N, White EP, Janowitz T. Cachexia: A systemic consequence of progressive, unresolved disease. Cell 2023; 186:1824-1845. [PMID: 37116469 PMCID: PMC11059056 DOI: 10.1016/j.cell.2023.03.028] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/15/2023] [Accepted: 03/23/2023] [Indexed: 04/30/2023]
Abstract
Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.
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Affiliation(s)
- Miriam Ferrer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; MRC Cancer Unit, University of Cambridge, Hutchison Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
| | - Tracy G Anthony
- Department of Nutritional Sciences, Rutgers School of Environmental and Biological Sciences, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Janelle S Ayres
- Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Giulia Biffi
- University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK
| | - Justin C Brown
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
| | - Bette J Caan
- Kaiser Permanente Northern California Division of Research, Oakland, CA 94612, USA
| | | | - Anthony P Coll
- Wellcome Trust-MRC Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Richard F Dunne
- University of Rochester Medical Center, University of Rochester, Rochester, NY 14642, USA
| | - Marcus D Goncalves
- Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jonas Grethlein
- Ruprecht Karl University of Heidelberg, Heidelberg 69117, Germany
| | - Steven B Heymsfield
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
| | - Sheng Hui
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
| | - Mariam Jamal-Hanjani
- Department of Medical Oncology, University College London Hospitals, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence and Cancer Metastasis Laboratory, University College London Cancer Institute, London WC1E 6DD, UK
| | - Jie Min Lam
- Cancer Research UK Lung Cancer Centre of Excellence and Cancer Metastasis Laboratory, University College London Cancer Institute, London WC1E 6DD, UK
| | - David Y Lewis
- The Beatson Institute for Cancer Research, Cancer Research UK, Glasgow G61 1BD, UK
| | - David McCandlish
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Karen M Mustian
- University of Rochester Medical Center, University of Rochester, Rochester, NY 14642, USA
| | - Stephen O'Rahilly
- Wellcome Trust-MRC Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Norbert Perrimon
- Department of Genetics, Blavatnik Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Eileen P White
- Rutgers Cancer Institute of New Jersey, Department of Molecular Biology and Biochemistry, Rutgers University, The State University of New Jersey, New Brunswick, NJ 08901, USA; Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY 11042, USA.
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Carnie LE, Shah D, Vaughan K, Kapacee ZA, McCallum L, Abraham M, Backen A, McNamara MG, Hubner RA, Barriuso J, Gillespie L, Lamarca A, Valle JW. Prospective Observational Study of Prevalence, Assessment and Treatment of Pancreatic Exocrine Insufficiency in Patients with Inoperable Pancreatic Malignancy (PANcreatic Cancer Dietary Assessment-PanDA). Cancers (Basel) 2023; 15:cancers15082277. [PMID: 37190204 DOI: 10.3390/cancers15082277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/07/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
INTRODUCTION Pancreatic exocrine insufficiency (PEI) in patients with advanced pancreatic cancer (aPC) is well documented, but there is no consensus regarding optimal screening. METHODS AND ANALYSIS Patients diagnosed with aPC referred for palliative therapy were prospectively recruited. A full dietetic assessment (including Mid-Upper Arm Circumference (MUAC), handgrip and stair-climb test), nutritional blood panel, faecal elastase (FE-1) and 13C-mixed triglyceride breath tests were performed. PRIMARY OBJECTIVE prevalence of dietitian-assessed PEI (demographic cohort (De-ch)); design (diagnostic cohort (Di-ch)) and validation (follow-up cohort (Fol-ch)) of a PEI screening tool. Logistic and Cox regressions were used for statistical analysis. RESULTS Between 1 July 2018 and 30 October 2020, 112 patients were recruited (50 (De-ch), 25 (Di-ch) and 37 (Fol-ch)). Prevalence of PEI (De-ch) was 64.0% (flatus (84.0%), weight loss (84.0%), abdominal discomfort (50.0%) and steatorrhea (48.0%)). The derived PEI screening panel (Di-ch) included FE-1 (normal/missing (0 points); low (1 point)) and MUAC (normal/missing (>percentile 25) (0 points); low (2 points)) and identified patients at high-risk (2-3 total points) of PEI [vs. low-medium risk (0-1 total points)]. When patients from the De-ch and Di-ch were analysed together, those classified by the screening panel as "high-risk" had shorter overall survival (multivariable Hazard Ratio (mHR) 1.86 (95% CI 1.03-3.36); p-value 0.040). The screening panel was tested in the Fol-ch; 78.4% patients classified as "high-risk", of whom 89.6% had dietitian-confirmed PEI. The panel was feasible for use in clinical practice (64.8% patients completed all assessments), with high acceptability (87.5% would repeat it). Most patients (91.3%) recommended dietetic input for all patients with aPC. CONCLUSIONS PEI is present in most patients with aPC; early dietetic input provides a holistic nutritional overview, including, but not limited to, PEI. This proposed screening panel may help to prioritise those at higher risk of PEI, requiring urgent dietitian input. Its prognostic role needs further validation.
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Affiliation(s)
- Lindsay E Carnie
- Nutrition & Dietetics, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Dinakshi Shah
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Kate Vaughan
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Zainul Abedin Kapacee
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | | | - Marc Abraham
- Nutrition & Dietetics, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Alison Backen
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Mairéad G McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Loraine Gillespie
- Nutrition & Dietetics, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK
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Araujo-Abad S, Manresa-Manresa A, Rodríguez-Cañas E, Fuentes-Baile M, García-Morales P, Mallavia R, Saceda M, de Juan Romero C. New therapy for pancreatic cancer based on extracellular vesicles. Biomed Pharmacother 2023; 162:114657. [PMID: 37023623 DOI: 10.1016/j.biopha.2023.114657] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC), is the most common aggressive cancer of the pancreas. The standard care of PDAC includes tumor resection and chemotherapy, but the lack of early diagnosis and the limited response to the treatment worsens the patient's condition. In order to improve the efficiency of chemotherapy, we look for more efficient systems of drug delivery. We isolated and fully characterized small Extracellular Vesicles (EVs) from the RWP-1 cell line. Our study indicates that the direct incubation method was the most efficient loading protocol and that a minimum total amount of drug triggers an effect on tumor cells. Therefore, we loaded the small EVs with two chemotherapeutic drugs (Temozolomide and EPZ015666) by direct incubation method and the amount of drug loaded was measured by high-performance liquid chromatography (HPLC). Finally, we tested their antiproliferative effect on different cancer cell lines. Moreover, the system is highly dependent on the drug structure and therefore RWP-1 small EVsTMZ were more efficient than RWP-1 small EVsEPZ015666. RWP-1 derived small EVs represent a promising drug delivery tool that can be further investigated in preclinical studies and its combination with PRMT5 inhibitor can be potentially developed in clinical trials for the treatment of PDAC.
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Affiliation(s)
- Salomé Araujo-Abad
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain; Centro de Biotecnología, Universidad Nacional de Loja, Avda. Pio Jaramillo Alvarado s/n, Loja, 110111 Loja, Ecuador
| | - Antonio Manresa-Manresa
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain
| | - Enrique Rodríguez-Cañas
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - María Fuentes-Baile
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain
| | - Pilar García-Morales
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - Ricardo Mallavia
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - Miguel Saceda
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain
| | - Camino de Juan Romero
- Unidad de Investigación, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO), Hospital General Universitario de Elche, Camí de l'Almazara 11, Elche, 03203 Alicante, Spain; Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Avda, Universidad s/n, Ed. Torregaitán, Elche, 03202 Alicante, Spain.
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Abnormal [ 18F]FDG uptake in liver and adipose tissue: a potential imaging biomarker for cancer-associated cachexia. Eur Radiol 2023; 33:2561-2573. [PMID: 36350393 DOI: 10.1007/s00330-022-09226-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 08/24/2022] [Accepted: 10/09/2022] [Indexed: 11/11/2022]
Abstract
OBJECTIVES This study aims to investigate and develop imaging biomarkers for the diagnosis of cancer-associated cachexia based on the organ and tissue-specific abnormal metabolisms measured by fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT. METHODS FDG PET/CT data from 390 cancer patients were analyzed retrospectively. Patients were divided into a development cohort and a validation cohort. Cachexia was defined as weight loss > 5% in 6 months or BMI < 20 and weight loss > 2%. According to the above definitions, patients were divided into cachexia and non-cachexia groups. Results of the clinical laboratory tests for metabolic levels and organ and tissue-specific FDG uptake obtained from the cachexia and non-cachexia groups were compared statistically. Logistic regression analysis was performed to identify independent variables associated with cachexia in the development cohort for generating the regression model. The performance of the model was tested using the data from a validation cohort and evaluated by area under the receiver operating characteristic curve (AUC). RESULTS Based on the data from the development cohort of 286 patients and a validation cohort of 104 patients, it is found that age, white blood cell count, peak standardized uptake value (SUV) of the liver, and minimum SUV of lean body mass of visceral fat and subcutaneous fat were independently associated with cachexia. The model incorporating these variables reached an AUC of 0.777 (95% confidence interval (CI): 0.721, 0.833) in the development cohort and an AUC of 0.729 (95% CI: 0.629, 0.829) in the validation cohort. CONCLUSION Organ and tissue-specific abnormal glucose metabolism as measured by PET/CT can be used as a biomarker for cancer-associated cachexia. KEY POINTS • Patients with cancer-associated cachexia have reduced FDG uptake in the liver and increased FDG uptake in visceral fat and subcutaneous fat. • FDG uptake of the liver, visceral fat, and subcutaneous fat can be independent risk factors for identifying cancer-associated cachexia. • Cancer-associated cachexia can be classified using the model that incorporates age, white blood cell count, FDG uptake of the liver, and visceral and subcutaneous fat can diagnose with an AUC of 0.729.
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Chang VT, Sandifer C, Zhong F. GI Symptoms in Pancreatic Cancer. Clin Colorectal Cancer 2023; 22:24-33. [PMID: 36623952 DOI: 10.1016/j.clcc.2022.12.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 12/21/2022] [Indexed: 12/31/2022]
Abstract
This review will apply a multidisciplinary approach to GI symptoms with attention to symptom assessment (instruments and qualitative aspects), differential diagnosis, and recent findings relevant to management of symptoms and underlying diseases. We conclude that further development of supportive interventions for GI symptoms for both patient and caregivers has the potential to reduce distress from GI symptoms, and anticipate better symptom control with advances in scientific knowledge and improvement of the evidence base.
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Affiliation(s)
- Victor T Chang
- Section Hematology Oncology (111), VA New Jersey Health Care System, East Orange, NJ; Department of Medicine, Rutgers - New Jersey Medical School, Newark, NJ.
| | | | - Fengming Zhong
- Section Hematology Oncology (111), VA New Jersey Health Care System, East Orange, NJ; Department of Medicine, Rutgers - New Jersey Medical School, Newark, NJ
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De Luca R, Gianotti L, Pedrazzoli P, Brunetti O, Rizzo A, Sandini M, Paiella S, Pecorelli N, Pugliese L, Pietrabissa A, Zerbi A, Salvia R, Boggi U, Casirati A, Falconi M, Caccialanza R. Immunonutrition and prehabilitation in pancreatic cancer surgery: A new concept in the era of ERAS® and neoadjuvant treatment. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:542-549. [PMID: 36577556 DOI: 10.1016/j.ejso.2022.12.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer (PC) is an aggressive disease, with a growing incidence, and a poor prognosis. Neoadjuvant treatments in PC are highly recommended in borderline resectable and recently in upfront resectable PC. PC is characterized by exocrine insufficiency and nutritional imbalance, leading to malnutrition/sarcopenia. The concept of malnutrition in PC is multifaceted, as the cancer-related alterations create an interplay with adverse effects of anticancer treatments. All these critical factors have a negative impact on the postoperative and oncological outcomes. A series of actions and programs can be implemented to improve resectable and borderline resectable PC in terms of postoperative complications, oncological outcomes and patients' quality of life. A timely nutritional evaluation and the implementation of appropriate evidence-based nutritional interventions in onco-surgical patients should be considered of importance to improve preoperative physical fitness. Unfortunately, nutritional care and its optimization are often neglected in real-world clinical practice. Currently available studies and ERAS® guidelines mostly support the use of pre- or perioperative medical nutrition, including immunonutrition, in order to decrease the rate of postoperative infections and length of hospital stay. Further data also suggest that medical nutrition should be considered proactively in PC patients, to possibly prevent severe malnutrition and its consequences on disease and treatment outcomes. This narrative review summarizes the most recent data related to the role of prehabilitation, ERAS® program, medical nutrition, and the timing of intervention on clinical outcomes of upfront resectable and borderline PC, and their potential implementation within the timeframe of neoadjuvant treatments.
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Affiliation(s)
- Raffaele De Luca
- Department of Surgical Oncology, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Luca Gianotti
- School of Medicine and Surgery, University of Milano-Bicocca, HPB Unit, San Gerardo Hospital, Monza, Italy.
| | - Paolo Pedrazzoli
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo and Department of Internal Medicine, University of Pavia, Pavia, Italy
| | - Oronzo Brunetti
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Alessandro Rizzo
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Marta Sandini
- Surgical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Salvatore Paiella
- General and Pancreatic Surgery Department, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Nicolò Pecorelli
- Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Luigi Pugliese
- Department of Surgery, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Andrea Pietrabissa
- Department of Surgery, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Alessandro Zerbi
- Pancreatic Surgery Unit, Humanitas Clinical and Research Center - IRCCS and Humanitas University - Department of Biomedical Sciences Rozzano, Milan, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery Department, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
| | - Ugo Boggi
- Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy
| | - Amanda Casirati
- Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Massimo Falconi
- Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Riccardo Caccialanza
- Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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49
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Lan X, Robin G, Kasnik J, Wong G, Abdel-Rahman O. Challenges in Diagnosis and Treatment of Pancreatic Exocrine Insufficiency among Patients with Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:1331. [PMID: 36831673 PMCID: PMC9953920 DOI: 10.3390/cancers15041331] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and is associated with an extremely poor prognosis. Many PDAC patients suffer from profound nutritional complications such as nutrient deficiencies, weight loss, malnutrition, and cancer cachexia. These complications cause barriers to effective anticancer treatments, gravely influence their quality of life, and decrease their overall survival. Pancreatic exocrine insufficiency (PEI) is defined as impaired digestion due to inadequate secretion of pancreatic enzymes and is a common cause of malnutrition in PDAC. This review first summarizes the existing literature around malnutrition in PDAC, with a particular focus on PEI and its management with pancreatic enzyme replacement therapy (PERT). Second, we summarize existing guidelines and recommendations for the management of PEI among patients with PDAC. Lastly, we highlight potential gaps of knowledge of PEI among healthcare providers resulting in underdiagnosis and treatment, which may have implications for the quality of life and overall survival of PDAC patients.
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Affiliation(s)
- Xiaoyang Lan
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Gabrielle Robin
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Jessica Kasnik
- Nutrition Services, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada
| | - Grace Wong
- Pharmacy Department, Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada
| | - Omar Abdel-Rahman
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada
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50
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Brooks A, Schumpp A, Dawson J, Andriello E, Fairman CM. Considerations for designing trials targeting muscle dysfunction in exercise oncology. Front Physiol 2023; 14:1120223. [PMID: 36866171 PMCID: PMC9972098 DOI: 10.3389/fphys.2023.1120223] [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: 12/09/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Individuals diagnosed with cancer commonly experience a significant decline in muscle mass and physical function collectively referred to as cancer related muscle dysfunction. This is concerning because impairments in functional capacity are associated with an increased risk for the development of disability and subsequent mortality. Notably, exercise offers a potential intervention to combat cancer related muscle dysfunction. Despite this, research is limited on the efficacy of exercise when implemented in such a population. Thus, the purpose of this mini review is to offer critical considerations for researchers seeking to design studies pertaining to cancer related muscle dysfunction. Namely, 1) defining the condition of interest, 2) determining the most appropriate outcome and methods of assessment, 3) establishing the best timepoint (along the cancer continuum) to intervene, and 4) understanding how exercise prescription can be configured to optimize outcomes.
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Affiliation(s)
- Alexander Brooks
- Exercise Oncology Laboratory, University of SC, Exercise Science, Columbia, SC, United States
| | - Alec Schumpp
- Exercise Oncology Laboratory, University of SC, Exercise Science, Columbia, SC, United States
| | - Jake Dawson
- Exercise Oncology Laboratory, University of SC, Exercise Science, Columbia, SC, United States
| | - Emily Andriello
- Exercise Oncology Laboratory, University of SC, Exercise Science, Columbia, SC, United States
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