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Diao B, Fan Z, Zhou B, Zhan H. Crosstalk between pancreatic cancer and adipose tissue: Molecular mechanisms and therapeutic implications. Biochem Biophys Res Commun 2024; 740:151012. [PMID: 39561650 DOI: 10.1016/j.bbrc.2024.151012] [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: 08/03/2024] [Revised: 11/02/2024] [Accepted: 11/14/2024] [Indexed: 11/21/2024]
Abstract
The incidence rate of pancreatic cancer, a fatal illness with a meager 5-year survival rate, has been on the rise in recent times. When individuals accumulate excessive amounts of adipose tissue, the adipose organ becomes dysfunctional due to alterations in the adipose tissue microenvironment associated with inflammation and metabolism. This phenomenon may potentially contribute to the aberrant accumulation of fat that initiates pancreatic carcinogenesis, thereby influencing the disease's progression, resistance to treatment, and metastasis. This review presents a summary of the impact of pancreatic steatosis, visceral fat, cancer-associated adipocytes and lipid diets on the advancement of pancreatic cancer, as well as the reciprocal effects of pancreatic cancer on adipose tissue. Understanding the molecular mechanisms underlying the relationship between dysfunctional adipose tissue and pancreatic cancer better may lead to the discovery of new therapeutic targets for the disease's prevention and individualized treatment. This is especially important given the rising global incidence of obesity, which will improve the pancreatic cancer treatment options that are currently insufficient.
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Affiliation(s)
- Boyu Diao
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Zhiyao Fan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Bin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Department of Retroperitoneal Tumor Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
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de Martin Coletti L, Segura GG, de Freitas LCG, de Souza Rangel Machado J, Beleboni R, Faccio A, Marins M, Fachin AL. ACVR2B polymorphism, Adiponectin, and GDF-15 levels as biomarkers for cachexia in gastrointestinal cancer. Sci Rep 2024; 14:27714. [PMID: 39533028 PMCID: PMC11557708 DOI: 10.1038/s41598-024-79176-7] [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: 08/05/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Reversing cancer cachexia remains a challenge. Genetic biomarkers for the early detection of the disease have been explored in order to enable the implementation of preventive measures. We therefore genotyped candidate genes based on cachexia phenotype and quantified adiponectin and GDF-15 levels in cachectic patients with gastrointestinal cancer. Patients with a diagnosis of gastrointestinal cancer were divided into a cachectic and a non-cachectic group after the start of chemotherapy. A control group (no cancer) was also included. We genotyped the following single nucleotide polymorphisms (SNPs) by quantitative PCR: FOXO3 (rs1935949), FOXO3 (rs4946935), ACVR2B (rs2268757), and SELP (rs6136). In addition, we quantified adiponectin and GDF-15 levels by ELISA. The rs2268757 SNP in the ACVR2B gene was associated with the weight loss phenotype in cachectic patients with gastrointestinal cancer (non-cachectic, P = 0.004). Plasma adiponectin levels were higher in cachectic patients compared to controls (P = 0.01) and non-cachectic patients (P = 0.004). GDF-15 was also elevated in cachectic patients compared to controls (P < 0.0001) and non-cachectic patients (P = 0.001). Analysis by sex showed elevated adiponectin levels in men (control, P = 0.01) and cachectic women (control, P = 0.04; non-cachectic, P = 0.01), as well as elevated GDF-15 levels in men (control, P = 0.002) and cachectic women (control, P = 0.002; non-cachectic, P = 0.007). However, there was no significant difference in the levels of these cytokines between cachectic men and women. The results suggest the rs2268757 SNP in the ACVR2B gene, adiponectin, and GDF-15 as potential biomarkers of cachexia in gastrointestinal cancer.
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Affiliation(s)
- Laura de Martin Coletti
- Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, 14096-900, Brazil
| | | | | | | | - Rene Beleboni
- Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, 14096-900, Brazil
| | - Adilson Faccio
- Instituto Ribeirãopretano de Combate ao Câncer, Ribeirão Preto, 14015-130, Brazil
| | - Mozart Marins
- Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, 14096-900, Brazil
| | - Ana Lúcia Fachin
- Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, 14096-900, Brazil.
- Biotechnology Unit, University of Ribeirão Preto, Av. Costábile Romano 2201, Ribeirão Preto, 14096-900, SP, Brazil.
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Klatte DCF, Weston A, Ma Y, Sledge H, Bali A, Bolan C, Engels M, van Hooft JE, van Leerdam ME, Ouni A, Wallace MB, Bi Y. Temporal Trends in Body Composition and Metabolic Markers Prior to Diagnosis of Pancreatic Ductal Adenocarcinoma. Clin Gastroenterol Hepatol 2024; 22:1830-1838.e9. [PMID: 38703880 DOI: 10.1016/j.cgh.2024.03.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND & AIMS Changes in body composition and metabolic factors may serve as biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to capture the longitudinal changes in body composition and metabolic factors before diagnosis of PDAC. METHODS We performed a retrospective cohort study in which all patients (≥18 years) diagnosed with PDAC from 2002 to 2021 were identified. We collected all abdominal computed tomography scans and 10 different blood-based biomarkers up to 36 months before diagnosis. We applied a fully automated abdominal segmentation algorithm previously developed by our group for 3-dimensional quantification of body composition on computed tomography scans. Longitudinal trends of body composition and blood-based biomarkers before PDAC diagnosis were estimated using linear mixed models, compared across different time windows, and visualized using spline regression. RESULTS We included 1690 patients in body composition analysis, of whom 516 (30.5%) had ≥2 prediagnostic computed tomography scans. For analysis of longitudinal trends of blood-based biomarkers, 3332 individuals were included. As an early manifestation of PDAC, we observed a significant decrease in visceral and subcutaneous adipose tissue (β = -1.94 [95% confidence interval (CI), -2.39 to -1.48] and β = -2.59 [95% CI, -3.17 to -2.02]) in area (cm2)/height (m2) per 6 months closer to diagnosis, accompanied by a decrease in serum lipids (eg, low-density lipoprotein [β = -2.83; 95% CI, -3.31 to -2.34], total cholesterol [β = -2.69; 95% CI, -3.18 to -2.20], and triglycerides [β = -1.86; 95% CI, -2.61 to -1.11]), and an increase in blood glucose levels. Loss of muscle tissue and bone volume was predominantly observed in the last 6 months before diagnosis. CONCLUSIONS This study identified significant alterations in a variety of soft tissue and metabolic markers that occur in the development of PDAC. Early recognition of these metabolic changes may provide an opportunity for early detection.
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Affiliation(s)
- Derk C F Klatte
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Alexander Weston
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida
| | - Yaohua Ma
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida
| | - Hanna Sledge
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida
| | - Aman Bali
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Candice Bolan
- Department of Radiology, Mayo Clinic, Jacksonville, Florida
| | - Megan Engels
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeanin E van Hooft
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Monique E van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands; Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ahmed Ouni
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Michael B Wallace
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Yan Bi
- Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
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Liu M, Ren Y, Zhou Z, Yang J, Shi X, Cai Y, Arreola AX, Luo W, Fung KM, Xu C, Nipp RD, Bronze MS, Zheng L, Li YP, Houchen CW, Zhang Y, Li M. The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia. Cancer Cell 2024; 42:885-903.e4. [PMID: 38608702 PMCID: PMC11162958 DOI: 10.1016/j.ccell.2024.03.009] [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: 08/26/2023] [Revised: 12/18/2023] [Accepted: 03/15/2024] [Indexed: 04/14/2024]
Abstract
With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
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Affiliation(s)
- Mingyang Liu
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Yu Ren
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Jingxuan Yang
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Xiuhui Shi
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Yang Cai
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Alex X Arreola
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Wenyi Luo
- Department of Pathology, Yale School of Medicine, New Haven, CT 06519, USA
| | - Kar-Ming Fung
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Chao Xu
- Department of Biostatistics and Epidemiology, Hudson College of Public Health, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Ryan D Nipp
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Michael S Bronze
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Lei Zheng
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Yi-Ping Li
- Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Courtney W Houchen
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Yuqing Zhang
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Min Li
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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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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Karneris A, Dedeilia A, Boland GM. Association of Sarcopenia with a Poor Prognosis and Decreased Tumor-Infiltrating CD8-Positive T Cells in Pancreatic Ductal Adenocarcinoma: A Retrospective Analysis. Ann Surg Oncol 2024; 31:16-18. [PMID: 37814185 DOI: 10.1245/s10434-023-14395-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 09/18/2023] [Indexed: 10/11/2023]
Affiliation(s)
- Anastasios Karneris
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Masuda S, Yamakawa K, Masuda A, Toyama H, Sofue K, Nanno Y, Komatsu S, Omiya S, Sakai A, Kobayashi T, Tanaka T, Tsujimae M, Ashina S, Gonda M, Abe S, Uemura H, Kohashi S, Inomata N, Nagao K, Harada Y, Miki M, Irie Y, Juri N, Kanzawa M, Itoh T, Fukumoto T, Kodama Y. Association of Sarcopenia with a Poor Prognosis and Decreased Tumor-Infiltrating CD8-Positive T Cells in Pancreatic Ductal Adenocarcinoma: A Retrospective Analysis. Ann Surg Oncol 2023; 30:5776-5787. [PMID: 37191859 PMCID: PMC10409680 DOI: 10.1245/s10434-023-13569-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/27/2023] [Indexed: 05/17/2023]
Abstract
BACKGROUND Sarcopenia, defined as a loss of skeletal muscle mass and quality, is found in 30-65% of patients with pancreatic ductal adenocarcinoma (PDAC) at diagnosis, and is a poor prognostic factor. However, it is yet to be evaluated why sarcopenia is associated with poor prognosis. Therefore, this study elucidated the tumor characteristics of PDAC with sarcopenia, including driver gene alterations and tumor microenvironment. PATIENTS AND METHODS We retrospectively analyzed 162 patients with PDAC who underwent pancreatic surgery between 2008 and 2017. We defined sarcopenia by measuring the skeletal muscle mass at the L3 level using preoperative computed tomography images and evaluated driver gene alteration (KRAS, TP53, CDKN2A/p16, and SMAD4) and tumor immune (CD4+, CD8+, and FOXP3+) and fibrosis status (stromal collagen). RESULTS In localized-stage PDAC (stage ≤ IIa), overall survival (OS) and recurrence-free survival were significantly shorter in the sarcopenia group than in the non-sarcopenia group (2-year OS 89.7% versus 59.1%, P = 0.03; 2-year RFS 74.9% versus 50.0%, P = 0.02). Multivariate analysis revealed that sarcopenia was an independent poor prognostic factor in localized-stage PDAC. Additionally, tumor-infiltrating CD8+ T cells in the sarcopenia group were significantly less than in the non-sarcopenia group (P = 0.02). However, no difference was observed in driver gene alteration and fib.rotic status. These findings were not observed in advanced-stage PDAC (stage ≥ IIb). CONCLUSIONS Sarcopenia was associated with a worse prognosis and decreased tumor-infiltrating CD8+ T cells in localized-stage PDAC. Sarcopenia may worsen a patient's prognosis by suppressing local tumor immunity.
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Affiliation(s)
- Shigeto Masuda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Kohei Yamakawa
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Atsuhiro Masuda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.
| | - Hirochika Toyama
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Keitaro Sofue
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yoshihide Nanno
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Shohei Komatsu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Satoshi Omiya
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Arata Sakai
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Takashi Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Takeshi Tanaka
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Masahiro Tsujimae
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Shigeto Ashina
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Masanori Gonda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Shohei Abe
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Hisahiro Uemura
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Shinya Kohashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Noriko Inomata
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Kae Nagao
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yoshiyuki Harada
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Mika Miki
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yosuke Irie
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Noriko Juri
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Maki Kanzawa
- Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoo Itoh
- Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takumi Fukumoto
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
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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: 7] [Impact Index Per Article: 3.5] [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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9
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Shakhshir M, Abushanab AS, Koni A, Barqawi A, Demyati K, Al-Jabi SW, Zyoud SH. Mapping the global research landscape on nutritional support for patients with gastrointestinal malignancy: visualization analysis. Support Care Cancer 2023; 31:179. [PMID: 36810807 DOI: 10.1007/s00520-023-07645-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 02/15/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND Early nutritional treatment is crucial for the care of patients with operable and advanced gastrointestinal malignancies. Therefore, much research has focused on nutritional support for patients with gastrointestinal malignancies. Therefore, this study aimed to evaluate the global scientific output and activity with respect to nutritional support and gastrointestinal malignancy. METHODS We searched in Scopus for publications on gastrointestinal cancer and nutritional assistance published between January 2002 and December 2021. Then, using VOSviewer 1.6.18 and Microsoft Excel 2013, we conducted bibliometric analysis and visualization. RESULTS A total of 906 documents were published between 2002 and 2021, including 740 original articles (81.68%) and 107 reviews (11.81%). China ranked first (298 publications, 32.89%), Japan ranked second (86 publications, 9.49%) and the USA ranked third (84 publications, 9.27%). The organisation with the highest number of publications was the Chinese Academy of Medical Sciences & Peking Union Medical College from China, with 14 articles, followed by the Peking Union Medical College Hospital from China and the Hospital Universitari Vall d'Hebron from Spain (13 publications for each). Before 2016, most studies focused on 'nutrition support for patients undergoing gastrointestinal surgery'. However, the latest trends showed that 'nutrition support and clinical outcomes in gastrointestinal malignancies' and 'malnutrition in patients with gastrointestinal cancer' would be more widespread in the future. CONCLUSIONS This review is the first bibliometric study to provide a thorough and scientific analysis of gastrointestinal cancer and nutritional support trends worldwide over the last 20 years. This study can aid researchers in decision-making by helping them understand the frontiers and hotspots in nutrition support and gastrointestinal cancer research. Future institutional and international collaboration is expected to accelerate the advancement of gastrointestinal cancer and nutritional support research and investigate more efficient treatment methods.
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Affiliation(s)
- Muna Shakhshir
- Department of Nutrition, An-Najah National University Hospital, Nablus, 44839, Palestine
| | - Amani S Abushanab
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
| | - Amer Koni
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
- Division of Clinical Pharmacy, Hematology and Oncology Pharmacy Department, An-Najah National University Hospital, Nablus, 44839, Palestine
| | - Abdelkarim Barqawi
- Department of Medicine, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
- Department of General Surgery, An-Najah National University Hospital, Nablus, 44839, Palestine
| | - Khaled Demyati
- Department of Medicine, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
- Department of General Surgery, An-Najah National University Hospital, Nablus, 44839, Palestine
| | - Samah W Al-Jabi
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine
| | - Sa'ed H Zyoud
- Department of Clinical and Community Pharmacy, College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine.
- Poison Control and Drug Information Center (PCDIC), College of Medicine and Health Sciences, An-Najah National University, Nablus, 44839, Palestine.
- Clinical Research Centre, An-Najah National University Hospital, Nablus, 44839, Palestine.
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10
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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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11
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Roberts DA, Watson E, Macdonald C, Khan Y, Prideaux S, Puthiyakunnel Saji A, Postaleniec E, Selvakumar J, Haghighat Ghahfarokhi M, Davidson B, Gurusamy K. Management of pain and cachexia in pancreatic cancer: Protocol for two systematic reviews, network meta-analysis, surveys and focus groups (Preprint). JMIR Res Protoc 2023; 12:e46335. [PMID: 37014692 PMCID: PMC10139686 DOI: 10.2196/46335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/26/2023] [Accepted: 02/26/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Approximately 75% of people with pancreatic cancer experience pain, and >50% of them have cachexia (weakness and wasting of the body). However, there is considerable uncertainty regarding the management of these distressing symptoms. OBJECTIVE Our primary objectives are to compare the relative benefits and harms of different interventions for pain in people with unresectable pancreatic cancer and for prevention and treatment of cachexia due to pancreatic cancer, through systematic reviews and network meta-analysis. Our secondary objectives are to develop an evidence-based clinical care pathway to manage pain and prevent and treat cachexia in people with pancreatic cancer through surveys and focus groups involving patients, carers, and health care professionals. METHODS We will perform 2 systematic reviews of the literature related to pain and cachexia in people with pancreatic cancer using searches from Cochrane Library, MEDLINE, Embase, Science Citation Index, and trial registries. Two researchers will independently screen for eligibility and identify randomized controlled trials (no language or publication status restriction), comparing interventions for pain or cachexia based on full-texts for articles shortlisted during screening. We will assess risk of bias in the trials using the Cochrane risk of bias tool (version 2.0) and obtain data related to baseline prognostic characteristics, potential effect modifiers and outcome data related to overall survival, health-related quality of life, treatment-related complications, and resource utilisation. We aim to conduct network meta-analysis on outcomes with multiple treatment comparisons where possible, otherwise, meta-analysis with direct comparisons, or narrative synthesis. We will perform various subgroup and sensitivity analyses. Using information obtained from both systematic reviews, we will conduct 2 surveys: one directed to patients or carers to assess acceptability of interventions, and the other to health care professionals to assess feasibility of delivery in the National Health Service. Four mixed focus groups will be conducted to evaluate findings and foster consensus in the development of the care pathway. RESULTS Funding was awarded from April 2022 (NIHR202727). Both systematic review protocols were prospectively registered on PROSPERO in May 2022. Formal searches began thereafter. Approval by the University College London Research Ethics Committee (23563/001) was received in December 2022. Data collection began in January 2023; data analysis will begin in May 2023 (completion expected by October 2023). CONCLUSIONS This study will comprehensively encompass major interventions for management of pain in people with unresectable pancreatic cancer, and prevention and treatment of cachexia in people with pancreatic cancer. Key stakeholders will facilitate the development of an evidence-based care pathway, ensuring both acceptability and feasibility. The project ends in April 2024 and published results are expected within 12 months of completion. We aim to present the findings through patient group websites, conferences, and publications, irrespective of the findings, in a peer-reviewed journal. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/46335.
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Affiliation(s)
- Danielle Amanda Roberts
- Division of Surgery and Interventional Science, Hampstead Campus, University College London, London, United Kingdom
| | - Eila Watson
- Supportive Cancer Care Research Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom
| | | | | | - Sarah Prideaux
- Patient and Public Involvement Representative, England, United Kingdom
| | | | - Emilia Postaleniec
- Leicester Medical School, The University of Leicester, Leicester, United Kingdom
| | - Jashan Selvakumar
- St George's, University of London Medical School, London, United Kingdom
| | | | - Brian Davidson
- Division of Surgery and Interventional Science, Hampstead Campus, University College London, London, United Kingdom
| | - Kurinchi Gurusamy
- Division of Surgery and Interventional Science, Hampstead Campus, University College London, London, United Kingdom
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12
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Yu YC, Ahmed A, Lai HC, Cheng WC, Yang JC, Chang WC, Chen LM, Shan YS, Ma WL. Review of the endocrine organ-like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:1057930. [PMID: 36465353 PMCID: PMC9713001 DOI: 10.3389/fonc.2022.1057930] [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: 09/30/2022] [Accepted: 10/26/2022] [Indexed: 08/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ-like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.
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Affiliation(s)
- Ying-Chun Yu
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Azaj Ahmed
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chung Cheng
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Juan-Chern Yang
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chun Chang
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Lu-Min Chen
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Yan-Shen Shan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Chen Kung University, Tainan, Taiwan
| | - Wen-Lung Ma
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
- Department of Nursing, Asia University, Taichung, Taiwan
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13
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Ścisło L, Bodys-Cupak I, Walewska E, Kózka M. Nutritional Status Indicators as Predictors of Postoperative Complications in the Elderly with Gastrointestinal Cancer. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:13453. [PMID: 36294035 PMCID: PMC9603671 DOI: 10.3390/ijerph192013453] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 06/16/2023]
Abstract
In patients scheduled for surgery, nutritional disorders worsen during the perioperative period, which is often a risk factor for postoperative complications. The aim of the study was to determine relationship between the preoperative nutritional status of elderly people with stomach, pancreatic and colon cancer and the incidence of postoperative complications and the length of hospital stay. The study included 143 patients with gastrointestinal cancer, aged 65-68, qualified for surgery. Mini Nutritional Assessment, body mass index questionnaires and medical records were used. Malnutrition was found in 9.8%, and a risk of malnutrition in 53.5% of the respondents. Body mass index showed overweight in 28% and obesity in 14% of the patients. Complications occurred in all types of nutritional status, the most common were those requiring intensive care unit treatment (36.8%), pancreatic and biliary fistulas (29.4%) and surgical site infections (58.2%). Gastric cancer patients at risk of malnutrition stayed longer in the hospital. Postoperative complications and longer hospital stays were observed more frequently in cases of overweight, obesity, malnutrition and its risk. Disturbances in the nutritional status, in the form of malnutrition and its risk, as well as overweight and obesity, determined more frequent occurrence of postoperative complications and longer hospital stay.
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Affiliation(s)
- Lucyna Ścisło
- Department of Clinical Nursing, Faculty of Health Sciences, Institute of Nursing and Midwifery, Jagiellonian University Medical College, 31-501 Krakow, Poland
| | - Iwona Bodys-Cupak
- Laboratory of Theory and Fundamentals of Nursing, Faculty of Health Sciences, Institute of Nursing and Midwifery, Jagiellonian University Medical College, 31-126 Krakow, Poland
| | - Elżbieta Walewska
- Department of Clinical Nursing, Faculty of Health Sciences, Institute of Nursing and Midwifery, Jagiellonian University Medical College, 31-501 Krakow, Poland
| | - Maria Kózka
- Department of Clinical Nursing, Faculty of Health Sciences, Institute of Nursing and Midwifery, Jagiellonian University Medical College, 31-501 Krakow, Poland
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14
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Lemecha M, Chalise JP, Takamuku Y, Zhang G, Yamakawa T, Larson G, Itakura K. Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia. Mol Metab 2022; 66:101612. [PMID: 36243318 PMCID: PMC9596731 DOI: 10.1016/j.molmet.2022.101612] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/22/2022] [Accepted: 10/10/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE Adipose tissue is the largest endocrine organ. When activated by cancer cells, adipocytes secrete adipocytokines and release fatty acids, which are then transferred to cancer cells and used for structural and biochemical support. How this metabolic symbiosis between cancer cells and adipocytes affects skeletal muscle and thermogenesis during cancer cachexia is unknown. Cancer cachexia is a multiorgan syndrome and how the communication between tissues is established has yet to be determined. We investigated adipose tissue secretory factors and explored their role in crosstalk of adipocytes, muscle, and tumor during pancreatic cancer cachexia. METHODS We used a pancreatic cancer cachexia mouse model generated by syngenic implantation of pancreatic ductal adenocarcinoma (PDAC) cells (KPC) intraperitoneally into C57BL/6 mice and Lcn2-knockout mice. For in vitro studies, adipocytes (3T3-L1 and primary adipocytes), cachectic cancer cells (Panc0203), non-cachectic cancer cells (Du145 cells), and skeletal muscle cells (C2C12 myoblasts) were used. RESULTS To identify molecules involved in the crosstalk of adipose tissue with muscle and tumors, we treated 3T3-L1 adipocytes with conditioned medium (CM) from cancer cells. Upon screening the secretomes from PDAC-induced adipocytes, several adipocytokines were identified, including lipocalin 2 (Lcn2). We investigated Lcn2 as a potential mediator of cachexia induced by adipocytes in response to PDAC. During tumor progression, mice exhibited a decline in body weight gain, which was accompanied by loss of adipose and muscle tissues. Tumor-harboring mice developed drastic hypothermia because of a dramatic loss of fat in brown adipose tissue (BAT) and suppression of the thermogenesis pathway. We inhibited Lcn2 with an anti-Lcn2 antibody neutralization or genomic ablation in mice. Lcn2 deficiency significantly improved body temperature in tumor-bearing mice, which was supported by the increased expression of Ucp1 and β3-adrenergic receptor in BAT. In addition, Lcn2 inhibition abrogated the loss of fat and muscle in tumor-bearing mice. In contrast to tumor-bearing WT mice, the corresponding Lcn2-knockout mice showed reduced ATGL expression in iWAT and decreased the expression of muscle atrophy molecular markers MuRF-1 and Fbx32. CONCLUSIONS This study showed that Lcn2 is causally involved in the dysregulation of adipose tissue-muscle-tumor crosstalk during pancreatic cancer cachexia. Therapeutic targets that suppress Lcn2 may minimize the progression of cachexia.
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Affiliation(s)
- Mengistu Lemecha
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA,Corresponding author. Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope 1500 E Duarte Rd, Duarte, CA 91010, USA.
| | - Jaya Prakash Chalise
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Yuki Takamuku
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA,Department of Central Research Institute, Wakunaga Pharmaceutical Co., Ltd., Akitakata, Hiroshima, Japan
| | - Guoxiang Zhang
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Takahiro Yamakawa
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Garrett Larson
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Keiichi Itakura
- Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
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15
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Adipose Tissue Wasting as a Determinant of Pancreatic Cancer-Related Cachexia. Cancers (Basel) 2022; 14:cancers14194754. [PMID: 36230682 PMCID: PMC9563866 DOI: 10.3390/cancers14194754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/20/2022] [Accepted: 09/27/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Pancreatic cancer (PC) is one of the deadliest cancers in the US. The poor prognosis of PC is related to diagnostic delay and the presence of unintended weight loss (cachexia) that commonly presents in PC patients even before diagnosis. However, the current understanding of how PC mediates cachexia is limited, and there are few treatments clinically available for cachexia. Based on the current literature, we demonstrate that PC-related cachexia primarily results from the wasting of adipose tissue, once thought to be merely a storage depot but now appreciated as an instrumental metabolic organ in the body. In addition, poor survival in PC patients was found to be associated with adipose tissue loss at diagnosis and during treatment. Therefore, identifying potential mediators and molecular mechanisms underlying adipose tissue loss would promise to pave the way for the development of effective interventions for PC-related cachexia Abstract Pancreatic cancer (PC) is the third leading cause of cancer-related death in the US, and its 5-year survival rate is approximately 10%. The low survival rates largely stem from diagnostic delay and the presence of significant adipose tissue and muscle wasting, commonly referred to as cachexia. Cachexia is present in nearly 80% of PC patients and is a key cause of poor response to treatment and about 20% of death in PC patients. However, there are few clinical interventions proven to be effective against PC-related cachexia. Different cancer types feature distinct secretome profiles and functional characteristics which would lead to cachexia development differently. Therefore, here we discuss affected tissues and potential mechanisms leading to cachexia in PC. We postulate that the most affected tissue during the development of PC-related cachexia is adipose tissue, historically and still thought to be just an inert repository for excess energy in relation to cancer-related cachexia. Adipose tissue loss is considerably greater than muscle loss in quantity and shows a correlation with poor survival in PC patients. Moreover, we suggest that PC mediates adipose atrophy by accelerating adipocyte lipid turnover and fibroblast infiltration.
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16
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Jo Y, Yeo MK, Dao T, Kwon J, Yi H, Ryu D. Machine learning-featured Secretogranin V is a circulating diagnostic biomarker for pancreatic adenocarcinomas associated with adipopenia. Front Oncol 2022; 12:942774. [PMID: 36059698 PMCID: PMC9428794 DOI: 10.3389/fonc.2022.942774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background Pancreatic cancer is one of the most fatal malignancies of the gastrointestinal cancer, with a challenging early diagnosis due to lack of distinctive symptoms and specific biomarkers. The exact etiology of pancreatic cancer is unknown, making the development of reliable biomarkers difficult. The accumulation of patient-derived omics data along with technological advances in artificial intelligence is giving way to a new era in the discovery of suitable biomarkers. Methods We performed machine learning (ML)-based modeling using four independent transcriptomic datasets, including GSE16515, GSE62165, GSE71729, and the pancreatic adenocarcinoma (PAC) dataset of the Cancer Genome Atlas. To find candidates for circulating biomarkers, we exported expression profiles of 1,703 genes encoding secretory proteins. Integrating three transcriptomic datasets into either a training or test set, ML-based modeling distinguishing PAC from normal was carried out. Another ML-model classifying long-lived and short-lived patients with PAC was also built to select prognosis-associated features. Finally, circulating level of SCG5 in the plasma was determined from the independent cohort (non-tumor = 25 and pancreatic cancer = 25). We also investigated the impact of SCG5 on adipocyte biology using recombinant protein. Results Three distinctive ML-classifiers selected 29-, 64- and 18-featured genes, recognizing the only common gene, SCG5. As per the prediction of ML-models, the SCG5 transcripts was significantly reduced in PAC and decreased further with the progression of the tumor, indicating its potential as a diagnostic as well as prognostic marker for PAC. External validation of SCG5 using plasma samples from patients with PAC confirmed that SCG5 was reduced significantly in patients with PAC when compared to controls. Interestingly, plasma SCG5 levels were correlated with the body mass index and age of donors, implying pancreas-originated SCG5 could regulate energy metabolism systemically. Additionally, analyses using publicly available Genotype-Tissue Expression datasets, including adipose tissue histology and pancreatic SCG5 expression, further validated the association between pancreatic SCG5 expression and the size of subcutaneous adipocytes in humans. However, we could not observe any definite effect of rSCG5 on the cultured adipocyte, in 2D in vitro culture. Conclusion Circulating SCG5, which may be associated with adipopenia, is a promising diagnostic biomarker for PAC.
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Affiliation(s)
- Yunju Jo
- Department of Molecular Cell Biology, Sungkyunkwan University (SKKU) School of Medicine, Suwon, South Korea
| | - Min-Kyung Yeo
- Department of Pathology, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Tam Dao
- Department of Molecular Cell Biology, Sungkyunkwan University (SKKU) School of Medicine, Suwon, South Korea
| | - Jeongho Kwon
- Department of Molecular Cell Biology, Sungkyunkwan University (SKKU) School of Medicine, Suwon, South Korea
| | - Hyon‐Seung Yi
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, South Korea
- *Correspondence: Hyon‐Seung Yi, ; Dongryeol Ryu,
| | - Dongryeol Ryu
- Department of Molecular Cell Biology, Sungkyunkwan University (SKKU) School of Medicine, Suwon, South Korea
- *Correspondence: Hyon‐Seung Yi, ; Dongryeol Ryu,
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17
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Hendifar A, Akinsola R, Muranaka H, Osipov A, Thomassian S, Moshayedi N, Yang J, Jacobs J, Devkota S, Bhowmick N, Gong J. Gut microbiome and pancreatic cancer cachexia: An evolving relationship. World J Gastrointest Oncol 2022; 14:1218-1226. [PMID: 36051103 PMCID: PMC9305570 DOI: 10.4251/wjgo.v14.i7.1218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/10/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Nearly 80% of patients with pancreatic ductal adenocarcinoma (PDAC) develop cachexia along their disease course. Cachexia is characterized by progressive weight loss, muscle wasting, and systemic inflammation and has been linked to poorer outcomes and impairments in quality of life. Management of PDAC cachexia has historically involved a multidisciplinary effort comprised of nutritional support, pancreatic enzyme replacement therapy, and/or pharmacologic interventions. Despite current interventions to mitigate PDAC cachexia, a significant proportion of patients continue to die from complications associated with cachexia underscoring the need for novel insights and treatments for this syndrome. We highlight the feasibility and effectiveness of a recent enteral feeding prospective trial at our institution to improve cachexia outcomes in patients with advanced PDAC. Additionally, we were among the first to characterize the stool microbiome composition in patients with advanced PDAC receiving enteral feeding for the treatment of cachexia. Novel insights into the relationship between enteral nutritional support, cachexia, and the gut microbiome are presented. These promising results are discussed in the context of a potential ability to modulate the stool microbiome as a new interventional strategy to mitigate PDAC cachexia.
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Affiliation(s)
- Andrew Hendifar
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Rasaq Akinsola
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Hayato Muranaka
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Arsen Osipov
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Shant Thomassian
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Natalie Moshayedi
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Julianne Yang
- The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, CA 90095, United States
| | - Jonathan Jacobs
- Department of Medicine, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, United States
| | - Suzanne Devkota
- Cedars-Sinai Medical Center, Department of Medicine, Inflammatory Bowel and Immunobiology Research Institute, University of California, Los Angeles, CA 90048, United States
| | - Neil Bhowmick
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Jun Gong
- Department of Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
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18
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Dang C, Wang M, Qin T, Qin R. How can we better predict the prognosis of patients with pancreatic cancer undergoing surgery using an immune-nutritional scoring system? Surgery 2022; 172:291-302. [PMID: 35086728 DOI: 10.1016/j.surg.2021.12.009] [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: 05/18/2021] [Revised: 12/10/2021] [Accepted: 12/14/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Several immune-nutritional scores have been used to predict the prognosis of pancreatic cancer, but the efficacies of these scores have yet to be compared. This study aimed to compare various immune-nutritional scores and establish a more accurate scoring system to evaluate the prognosis of pancreatic cancer. METHODS The preoperative immune-nutritional scores of 411 patients with pancreatic cancer who underwent radical surgery were retrospectively compared. The cut-off point for predicting mortality was determined using X-tile analysis. The efficacies of various immune-nutritional scores for predicting the short- and long-term outcomes of pancreatic cancer were compared. A new nomogram was established based on immune-nutritional scores. RESULTS Regardless of the immune-nutritional scoring method, the short- and long-term outcomes of the group with better nutritional status were better than those of the other groups. The modified Glasgow prognosis score (C-index = 0.74) and controlling nutritional status score (C-index = 0.61) were more effective for predicting the prognosis of pancreatic cancer. A nomogram based on controlling nutritional status, red blood cell distribution, modified Glasgow prognosis score, and tumor node metastasis classification stage was more accurate than any single immune-nutritional score for predicting pancreatic cancer prognosis (C-index = 0.78). CONCLUSION Patients with pancreatic cancer with poor preoperative nutritional status have a poorer prognosis. We identify a new nomogram based on immune-nutritional scores that provides an accurate and individualized prediction of prognosis for pancreatic cancer.
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Affiliation(s)
- Chao Dang
- Department of Pancreatic-Biliary Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Wang
- Department of Pancreatic-Biliary Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Qin
- Department of Pancreatic-Biliary Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Renyi Qin
- Department of Pancreatic-Biliary Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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19
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A Review of the Clinical Implications of Cachexia, Sarcopenia, and BMI in Patients with Peritoneal Carcinomatosis Receiving Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. Cancers (Basel) 2022; 14:cancers14122853. [PMID: 35740519 PMCID: PMC9221457 DOI: 10.3390/cancers14122853] [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: 05/11/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Patients with peritoneal carcinomatosis from varying cancers may be affected by weight loss and decreased muscle mass, the hallmarks of cachexia. These patients can undergo surgical management via cytoreductive surgery and hyperthermic intraperitoneal chemotherapy to improve their overall survival. Here, we review the current literature investigating the impact of sarcopenia, cachexia, and body mass index on outcomes in a patient population that undergo surgical treatment. The results vary across the studies suggesting that further investigation is necessary to better understand the impact of these entities on postoperative outcomes and survival. Abstract Peritoneal carcinomatosis (PC) is the dissemination of cancer throughout the peritoneal cavity. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the surgical treatment of choice in highly selected patients. The aim of this narrative review was to assess the impact of cachexia, sarcopenia, and body mass index (BMI) on patient outcomes for patients undergoing CRS and HIPEC for peritoneal carcinomatosis. A narrative review was performed and articles pertaining to cachexia, sarcopenia, BMI, peritoneal carcinomatosis, and CRS/HIPEC were reviewed and selected. In total, 3041 articles were screened and seven original studies met the inclusion criteria. In summary, obesity was found to not be a contraindication to surgery, but the impact of BMI was variable across the spectrum. Decreased skeletal muscle mass was found to be associated with poorer postoperative outcomes in three studies and with worse overall survival in two. With limited data, evaluating the impact of BMI, sarcopenia, and cachexia on patients with PC undergoing CRS and HIPEC was difficult as most studies included heterogeneous cancer patient populations; thus, postoperative outcomes and survival were inconsistent across studies. More research is needed to better understand its impact and to better generalize the results for each cancer subset treated with CRS and HIPEC across diverse patient populations.
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20
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Review of Mechanisms and Treatment of Cancer-Induced Cardiac Cachexia. Cells 2022; 11:cells11061040. [PMID: 35326491 PMCID: PMC8947347 DOI: 10.3390/cells11061040] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/14/2022] [Accepted: 03/17/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer cachexia is a multifactorial, paraneoplastic syndrome that impacts roughly half of all cancer patients. It can negatively impact patient quality of life and prognosis by causing physical impairment, reducing chemotherapy tolerance, and precluding them as surgical candidates. While there is substantial research on cancer-induced skeletal muscle cachexia, there are comparatively fewer studies and therapies regarding cardiac cachexia in the setting of malignancy. A literature review was performed using the PubMed database to identify original articles pertaining to cancer-induced cardiac cachexia, including its mechanisms and potential therapeutic modalities. Seventy studies were identified by two independent reviewers based on inclusion and exclusion criteria. While there are multiple studies addressing the pathophysiology of cardiac-induced cancer cachexia, there are no studies evaluating therapeutic options in the clinical setting. Many treatment modalities including nutrition, heart failure medication, cancer drugs, exercise, and gene therapy have been explored in in vitro and mice models with varying degrees of success. While these may be beneficial in cancer patients, further prospective studies specifically focusing on the assessment and treatment of the cardiac component of cachexia are needed.
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21
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Dasgupta A, Arneson-Wissink PC, Schmitt RE, Cho DS, Ducharme AM, Hogenson TL, Krueger EW, Bamlet WR, Zhang L, Razidlo GL, Fernandez-Zapico ME, Doles JD. Anticachectic regulator analysis reveals Perp-dependent antitumorigenic properties of 3-methyladenine in pancreatic cancer. JCI Insight 2022; 7:153842. [PMID: 34874916 PMCID: PMC8855816 DOI: 10.1172/jci.insight.153842] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 12/01/2021] [Indexed: 12/14/2022] Open
Abstract
Approximately 80% of pancreatic cancer patients suffer from cachexia, and one-third die due to cachexia-related complications such as respiratory failure and cardiac arrest. Although there has been considerable research into cachexia mechanisms and interventions, there are, to date, no FDA-approved therapies. A major contributing factor for the lack of therapy options could be the failure of animal models to accurately recapitulate the human condition. In this study, we generated an aged model of pancreatic cancer cachexia to compare cachexia progression in young versus aged tumor-bearing mice. Comparative skeletal muscle transcriptome analyses identified 3-methyladenine (3-MA) as a candidate antiwasting compound. In vitro analyses confirmed antiwasting capacity, while in vivo analysis revealed potent antitumor effects. Transcriptome analyses of 3-MA-treated tumor cells implicated Perp as a 3-MA target gene. We subsequently (a) observed significantly higher expression of Perp in cancer cell lines compared with control cells, (b) noted a survival disadvantage associated with elevated Perp, and (c) found that 3-MA-associated Perp reduction inhibited tumor cell growth. Finally, we have provided in vivo evidence that survival benefits conferred by 3-MA administration are independent of its effect on tumor progression. Taken together, we report a mechanism linking 3-MA to Perp inhibition, and we further implicate Perp as a tumor-promoting factor in pancreatic cancer.
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Affiliation(s)
| | | | | | | | | | - Tara L. Hogenson
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology
| | - Eugene W. Krueger
- Department of Biochemistry and Molecular Biology,,Division of Gastroenterology and Hepatology
| | | | - Lizhi Zhang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gina L. Razidlo
- Department of Biochemistry and Molecular Biology,,Division of Gastroenterology and Hepatology
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22
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Evaluating the Khorana risk score of gastrointestinal cancer patients during initial chemotherapy as a predictor of patient mortality: A retrospective study. J Cardiol 2021; 79:655-663. [PMID: 34924239 DOI: 10.1016/j.jjcc.2021.11.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND The Khorana risk score (KRS) has been recommended for predicting the incidence of cancer-associated thrombosis (CAT). However, it has been reported KRS was not useful in predicting CAT, but rather in predicting death by setting high scores for the primary tumor site or a low prevalence of severe obesity. METHODS A total of 260 consecutive patients with no history of thrombosis and who started initial chemotherapy for gastrointestinal cancer from January 2017 to December 2018 at our hospital were divided into three groups according to KRS; they were observed until December 2019 [122 patients (46.9%) in the low-risk group, 114 patients (43.8%) in the intermediate-risk group, and 24 patients (9.2%) in the high-risk group]. The incidence of CAT and all-cause death were compared among the three groups. RESULTS The median age of the patients was 67 years; 63.5% were men. CAT was observed in 61 patients (26.1%); 84 patients (37.9%) died during the observation period. The incidence rate of CAT was similar among the three groups (log-rank p = 0.4); but all-cause death showed a significant difference among the three groups (high-risk group: 58.2%, intermediate-risk group: 44.6%, low-risk group: 27.5%, log-rank p = 0.002). In the multivariate analysis, the high-risk KRS group remained at increased risk for all-cause death (HR, 2.83; 95% CI, 1.37-5.83; p = 0.005), but not with CAT. CONCLUSIONS The KRS at the start of chemotherapy for gastrointestinal cancer is not effective in predicting CAT, but it is effective in predicting prognosis in patients with gastrointestinal cancer.
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23
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Rossmeislová L, Gojda J, Smolková K. Pancreatic cancer: branched-chain amino acids as putative key metabolic regulators? Cancer Metastasis Rev 2021; 40:1115-1139. [PMID: 34962613 DOI: 10.1007/s10555-021-10016-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/18/2021] [Indexed: 02/06/2023]
Abstract
Branched-chain amino acids (BCAA) are essential amino acids utilized in anabolic and catabolic metabolism. While extensively studied in obesity and diabetes, recent evidence suggests an important role for BCAA metabolism in cancer. Elevated plasma levels of BCAA are associated with an increased risk of developing pancreatic cancer, namely pancreatic ductal adenocarcinoma (PDAC), a tumor with one of the highest 1-year mortality rates. The dreadful prognosis for PDAC patients could be attributable also to the early and frequent development of cancer cachexia, a fatal host metabolic reprogramming leading to muscle and adipose wasting. We propose that BCAA dysmetabolism is a unifying component of several pathological conditions, i.e., obesity, insulin resistance, and PDAC. These conditions are mutually dependent since PDAC ranks among cancers tightly associated with obesity and insulin resistance. It is also well-established that PDAC itself can trigger insulin resistance and new-onset diabetes. However, the exact link between BCAA metabolism, development of PDAC, and tissue wasting is still unclear. Although tissue-specific intracellular and systemic metabolism of BCAA is being intensively studied, unresolved questions related to PDAC and cancer cachexia remain, namely, whether elevated circulating BCAA contribute to PDAC etiology, what is the biological background of BCAA elevation, and what is the role of adipose tissue relative to BCAA metabolism during cancer cachexia. To cover those issues, we provide our view on BCAA metabolism at the intracellular, tissue, and whole-body level, with special emphasis on different metabolic links to BCAA intermediates and the role of insulin in substrate handling.
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Affiliation(s)
- Lenka Rossmeislová
- Department of Pathophysiology, Center for Research On Nutrition, Metabolism, and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Franco-Czech Laboratory for Clinical Research On Obesity, Third Faculty of Medicine, Prague, Czech Republic
| | - Jan Gojda
- Franco-Czech Laboratory for Clinical Research On Obesity, Third Faculty of Medicine, Prague, Czech Republic
- Department of Internal Medicine, Královské Vinohrady University Hospital and Third Faculty of Medicine, Prague, Czech Republic
| | - Katarína Smolková
- Laboratory of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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24
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Gresham G, Placencio‐Hickok VR, Lauzon M, Nguyen T, Kim H, Mehta S, Paski S, Pandol SJ, Osipov A, Gong J, Jamil LH, Nissen N, Lo SK, Hendifar AE. Feasibility and efficacy of enteral tube feeding on weight stability, lean body mass, and patient-reported outcomes in pancreatic cancer cachexia. J Cachexia Sarcopenia Muscle 2021; 12:1959-1968. [PMID: 34609081 PMCID: PMC8718084 DOI: 10.1002/jcsm.12799] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 08/06/2021] [Accepted: 08/23/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Advanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. This wasting has been linked to poor survival outcomes, alterations in host defenses, decreased functional ability, and diminished health-related quality of life (HRQOL) in pancreatic cancer patients. There are currently no standardized approaches to the management of pancreatic cancer cachexia. This study explores the feasibility and efficacy of enteral tube feeding of a peptide-based formula to improve weight stability and patient-reported outcomes (PROs) in advanced PDAC patients with cachexia. METHODS This was a single-institution, single-arm prospective trial conducted between April 2015 and March 2019. Eligible patients were adults (>18 years) diagnosed with advanced or locally advanced PDAC and cachexia, defined as greater than 5% unexplained weight loss within 6 months from screening. The study intervention included three 28 day cycles of a semi-elemental peptide-based formula, administered through a jejunal or gastrojejunal feeding tube. The primary outcome was weight stability at 3 months (Cycle 3), defined as weight change less than 0.1 kg/baseline BMI unit from baseline. Secondary outcomes included changes in lean body mass, appendicular lean mass, bone mineral density, fat mass, and percent body fat, as measured with a DEXA scan, HRQOL (EORTC QLQC30) and NIH PROMIS PROs assessed at each cycle. Daily activity (steps, distance, active minutes, heart rate, and sleep) were remotely monitored using a wearable activity monitor (Fitbit) over the 3 month study period. RESULTS Thirty-six patients were screened for eligibility, 31 patients consented onto study and underwent jejunal tube placement, and 16 patients completed treatment: mean age 67 years (SD 9.3), 43.8% male. Among evaluable patients (n = 16), weight stability was achieved in 10 patients (62.5%), thus completing the trial early. Increases in lean body mass (1273.1, SD: 4078, P = 0.01) and appendicular lean mass (0.45, SD: 0.6, P = 0.02) were observed. Statistically significant improvements at Cycle 3 from baseline were also observed for QLQC30 role function [mean difference (MD): 20.1, P = 0.03], appetite (MD: 27.4, P = 0.02), and global health scores (MD: 13.3, P = 0.05) as well as for NIH PROMIS t-scores for depression (MD: -10.4, P = 0.006) and pain interference (MD: -7.5, P = 0.05). Objectively monitored (Fitbit) activity levels increased, although statistical significance was not reached. CONCLUSIONS Our findings suggest that enteral nutrition support may improve weight stability, lean body mass, appendicular lean mass and PROs in PDAC patients with cachexia who completed treatment, representing a subsample of the study population. The feasibility and role of enteral feeding in routine care remain unclear, and larger and randomized controlled trials are warranted.
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Affiliation(s)
- Gillian Gresham
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | | | - Marie Lauzon
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Tyra Nguyen
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Haesoo Kim
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Sejal Mehta
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Shirley Paski
- Department of Medicine, Karsh Division of Gastroenterology and HepatologyCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Stephen J. Pandol
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Arsen Osipov
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Jun Gong
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Laith H. Jamil
- Section of Gastroenterology and HepatologyBeaumont HealthRoyal OakMIUSA
- Oakland University William Beaumont School of MedicineRochesterMIUSA
| | - Nicholas Nissen
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Simon K. Lo
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Andrew E. Hendifar
- Department of MedicineSamuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical CenterLos AngelesCAUSA
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25
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Rovesti G, Valoriani F, Rimini M, Bardasi C, Ballarin R, Di Benedetto F, Menozzi R, Dominici M, Spallanzani A. Clinical Implications of Malnutrition in the Management of Patients with Pancreatic Cancer: Introducing the Concept of the Nutritional Oncology Board. Nutrients 2021; 13:3522. [PMID: 34684523 PMCID: PMC8537095 DOI: 10.3390/nu13103522] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer represents a very challenging disease, with an increasing incidence and an extremely poor prognosis. Peculiar features of this tumor entity are represented by pancreatic exocrine insufficiency and an early and intense nutritional imbalance, leading to the highly prevalent and multifactorial syndrome known as cancer cachexia. Recently, also the concept of sarcopenic obesity has emerged, making the concept of pancreatic cancer malnutrition even more multifaceted and complex. Overall, these nutritional derangements play a pivotal role in contributing to the dismal course of this malignancy. However, their relevance is often underrated and their assessment is rarely applied in clinical daily practice with relevant negative impact for patients' outcome in neoadjuvant, surgical, and metastatic settings. The proper detection and management of pancreatic cancer-related malnutrition syndromes are of primary importance and deserve a specific and multidisciplinary (clinical nutrition, oncology, etc.) approach to improve survival, but also the quality of life. In this context, the introduction of a "Nutritional Oncology Board" in routine daily practice, aimed at assessing an early systematic screening of patients and at implementing nutritional support from the time of disease diagnosis onward seems to be the right path to take.
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Affiliation(s)
- Giulia Rovesti
- Division of Oncology, Department of Medical and Surgical Sciences of Children and Adults, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (M.R.); (C.B.); (M.D.)
| | - Filippo Valoriani
- Division of Metabolic Diseases and Clinical Nutrition, Department of Specialistic Medicines, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (F.V.); (R.M.)
| | - Margherita Rimini
- Division of Oncology, Department of Medical and Surgical Sciences of Children and Adults, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (M.R.); (C.B.); (M.D.)
| | - Camilla Bardasi
- Division of Oncology, Department of Medical and Surgical Sciences of Children and Adults, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (M.R.); (C.B.); (M.D.)
| | - Roberto Ballarin
- Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Department of General Surgery, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (R.B.); (F.D.B.)
| | - Fabrizio Di Benedetto
- Division of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Department of General Surgery, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (R.B.); (F.D.B.)
| | - Renata Menozzi
- Division of Metabolic Diseases and Clinical Nutrition, Department of Specialistic Medicines, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (F.V.); (R.M.)
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences of Children and Adults, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (M.R.); (C.B.); (M.D.)
| | - Andrea Spallanzani
- Division of Oncology, Department of Medical and Surgical Sciences of Children and Adults, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy; (M.R.); (C.B.); (M.D.)
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26
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Arneson-Wissink PC, Doles JD. Disrupted NOS2 metabolism drives myoblast response to wasting-associated cytokines. Exp Cell Res 2021; 407:112779. [PMID: 34428455 PMCID: PMC8440454 DOI: 10.1016/j.yexcr.2021.112779] [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: 06/08/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/14/2022]
Abstract
Skeletal muscle wasting drives negative clinical outcomes and is associated with a spectrum of pathologies including cancer. Cancer cachexia is a multi-factorial syndrome that encompasses skeletal muscle wasting and remains understudied, despite being a frequent and serious co-morbidity. Deviation from the homeostatic balance between breakdown and regeneration leads to muscle wasting disorders, such as cancer cachexia. Muscle stem cells (MuSCs) are the cellular compartment responsible for muscle regeneration, which makes MuSCs an intriguing target in the context of wasting muscle. Molecular studies investigating MuSCs and skeletal muscle wasting largely focus on transcriptional changes, but our group and others propose that metabolic changes are another layer of cellular regulation underlying MuSC dysfunction in cancer cachexia. In the present study, we combined gene expression and non-targeted metabolomic profiling of myoblasts exposed to wasting conditions (cancer cell conditioned media, CC-CM) to derive a more complete picture of the myoblast response to wasting factors. After mapping these features to annotated pathways, we found that more than half of the mapped pathways were amino acid-related, linking global amino acid metabolic disruption to conditioned media-induced myoblast defects. Notably, arginine metabolism was a highly enriched pathway in combined metabolomic and transcriptomic data. Arginine catabolism generates nitric oxide (NO), an important signaling molecule known to have negative effects on mature muscle. We hypothesize that tumor-derived disruptions in Nitric Oxide Synthase (NOS)2-regulated arginine catabolism impair differentiation of MuSCs. The work presented here further investigates the effect of NOS2 overactivity on myoblast proliferation and differentiation. We show that NOS2 inhibition is sufficient to rescue wasting phenotypes associated with inflammatory cytokines. Ultimately, this work provides new insights into MuSC biology and opens up potential therapeutic avenues for addressing disrupted MuSC dynamics in cancer cachexia.
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Affiliation(s)
- Paige C Arneson-Wissink
- Department of Biochemistry and Molecular Biology, Mayo
Clinic, Rochester, Minnesota, 55905 USA
| | - Jason D Doles
- Department of Biochemistry and Molecular Biology, Mayo
Clinic, Rochester, Minnesota, 55905 USA.,Corresponding Author: Jason D Doles, Department of
Biochemistry and Molecular Biology, Mayo Clinic, 200 First St SW, Guggenheim
16-11A1, Rochester, MN 55905, Tel: (507) 284-9372, Fax: (507) 284-3383,
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27
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Tanţău A, Leucuţa DC, Tanţău M, Boţan E, Zaharie R, Mândruţiu A, Tomuleasa IC. Inflammation, Tumoral Markers and Interleukin-17, -10, and -6 Profiles in Pancreatic Adenocarcinoma and Chronic Pancreatitis. Dig Dis Sci 2021; 66:3427-3438. [PMID: 33184795 DOI: 10.1007/s10620-020-06700-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 10/27/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Interleukin profiles can be used as biochemical markers regarding the early diagnosis of pancreatic cancer. AIMS To assess CRP, CA 19-9, CEA levels, and interleukin-6, -10, and -17 profiles in pancreatic ductal adenocarcinoma, chronic pancreatitis was compared with a control group, and the correlation with pancreatic cancer survival. METHODS A total of 87 patients were prospective divided in pancreatic cancer (n = 53), chronic pancreatitis (n = 22) ,and control group (n = 12). The diagnosis of PDAC was made histologically. The diagnosis of chronic pancreatitis was based on medical history, imaging methods, and endoscopic ultrasound. Systemic concentrations of interleukins were measured using ELISA kits. The patients were followed at 1, 3, and 6 months. RESULTS CRP, CA 19-9, and CEA were higher in the pancreatic cancer group (p < 0.001). Interleukin-10 was significantly higher in the pancreatic cancer and chronic pancreatitis groups (p < 0.001). Interleukin-17 was statistically higher in the pancreatic cancer group (p < 0.0001). The cut-off of interleukin-17 of 0.273 had a sensitivity of 90.9 and a specificity of 80.9 with a curve under ROC of 0.80 in order to differentiate between pancreatic cancer and chronic pancreatitis. The serum levels of interleukins are not correlated with the stage of the disease. CRP, CA 19-9, CEA, and interleukin-6, -10, and -17 were lower in patients with survival more than 6 months. CONCLUSIONS We detected high levels of interleukin-6, -10, and -17 in chronic pancreatitis and pancreatic cancer. Serum interleukin-17 levels can discriminate between pancreatic cancer and chronic pancreatitis. The prognostic role of interleukins needs to be established.
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Affiliation(s)
- Alina Tanţău
- The 4th Medical Clinic, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400015, Cluj-Napoca City, Cluj, Romania
- Department of Gastroenterology and Hepatology Medical Center, 400132, Cluj-Napoca City, Cluj, Romania
| | - Daniel-Corneliu Leucuţa
- Medical Informatics and Biostatistics Department, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012, Cluj-Napoca City, Cluj, Romania.
| | - Marcel Tanţău
- The 3rd Medical Clinic, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012, Cluj-Napoca City, Cluj, Romania
- Department of Internal Medicine and Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400158, Cluj-Napoca City, Cluj, Romania
| | - Emil Boţan
- Anatomopathology Department, "Regina Maria" Medical Center, 400117, Cluj-Napoca City, Cluj, Romania
| | - Roxana Zaharie
- The 3rd Medical Clinic, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012, Cluj-Napoca City, Cluj, Romania
- Department of Internal Medicine and Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400158, Cluj-Napoca City, Cluj, Romania
| | - Alina Mândruţiu
- Department of Gastroenterology and Hepatology Medical Center, 400132, Cluj-Napoca City, Cluj, Romania
| | - Ionuţ-Ciprian Tomuleasa
- Hematology Department, "Prof. Dr. Ion Chiricuţă" Institute of Oncology Cluj-Napoca, 400015, Cluj-Napoca City, Cluj, Romania
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Dong J, Yu J, Li Z, Gao S, Wang H, Yang S, Wu L, Lan C, Zhao T, Gao C, Liu Z, Wang X, Hao J. Serum insulin-like growth factor binding protein 2 levels as biomarker for pancreatic ductal adenocarcinoma-associated malnutrition and muscle wasting. J Cachexia Sarcopenia Muscle 2021; 12:704-716. [PMID: 33763996 PMCID: PMC8200427 DOI: 10.1002/jcsm.12692] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Malnutrition and muscle wasting are common features frequently observed in pancreatic ductal adenocarcinoma (PDAC) patients with cancer cachexia. They are associated with reduced survival and quality of life. Nutrition therapy is an important part of multimodal cancer care in PDAC. However, due to the complexity of nutrition assessment, only 30-60% of patients with nutritional risks receive nutritional treatment at present. It is important to identify biomarkers that may be used to improve management of PDAC-associated malnutrition. Serum insulin-like growth factor binding protein 2 (IGFBP2) has emerged as a potential serum biomarker in a variety of tumours. However, its association with malnutrition and muscle wasting in PDAC is unclear. METHODS We evaluated the tumour IGFBP2 expression and serum IGFBP2 level in 98 PDAC patients using immunohistochemistry and enzyme-linked immunosorbent assay and analysed the correlation between them. Furthermore, we explored the relationship between IGFBP2 of both tumour and serum and nutritional status (Patient-Generated Subjective Global Assessment and skeletal muscle index). Pan02 IGFBP2 stable transfection cell lines, Pan02 PLV-IGFBP2 cells, and PLKO-IGFBP2 cells were injected subcutaneously into the flank of C57BL/6 mouse. Serum IGFBP2 levels, food intake, and body weight of these mice were measured. The degree of muscle atrophy is characterized by haematoxylin and eosin, Oil Red O, and Masson's trichrome staining. The mRNA and protein expression of several essential muscle-related signal proteins such as atrogin-1 and muscle RING finger 1 was measured. RESULTS Among 98 patients, we found that tumour IGFBP2 expression is related to plasma IGFBP2 levels (rs = 0.562, P < 0.001), and they significantly increased among patients with Patient-Generated Subjective Global Assessment ≥9 and correlated with overall survival. Moreover, serum IGFBP2 level is negatively correlated with skeletal muscle index (rs = -0.600, P < 0.001) and Hounsfield units (rs = -0.532, P < 0.001). In mice injected with Pan02 PLV-IGFBP2 cell, circulating IGFBP2 was elevated while body weight and food intake were decreased when compared with Pan02 PLV-Control group. These mice also exhibited significantly aggravated muscle fibre atrophy, lipid deposition, and increased collagen tissue, and the expression of mRNA and protein of atrogin-1 and muscle RING finger 1 in the gastrocnemius muscle is increased. Conversely, these symptoms were alleviated in the PLKO-IGFBP2 group. CONCLUSIONS In the current study, there is a significant correlation between serum IGFBP2 levels, malnutrition, and muscle atrophy in PDAC. Our results suggested that serum IGFBP2 level might be a promising biomarker and intervention targets for PDAC-associated severe malnutrition and muscle wasting.
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Affiliation(s)
- Jie Dong
- Department of Nutrition Therapy, Tianjin Medical University Cancer Institute and Hospital/National Clinical Research Center for Cancer/Key Laboratory of Cancer Prevention and Therapy, Tianjin/Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jie Yu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China.,Department of General Surgery, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Zekun Li
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Song Gao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Hongwei Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Shengyu Yang
- Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - Liangliang Wu
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Chungen Lan
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Tiansuo Zhao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Chuntao Gao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Zhe Liu
- The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Xiuchao Wang
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
| | - Jihui Hao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Huanhu West Road, Hexi District, Tianjin, 300060, China
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Salinas-Miranda E, Deniffel D, Dong X, Healy GM, Khalvati F, O'Kane GM, Knox J, Bathe OF, Baracos VE, Gallinger S, Haider MA. Prognostic value of early changes in CT-measured body composition in patients receiving chemotherapy for unresectable pancreatic cancer. Eur Radiol 2021; 31:8662-8670. [PMID: 33934171 DOI: 10.1007/s00330-021-07899-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/27/2021] [Accepted: 03/16/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Skeletal muscle mass is a prognostic factor in pancreatic ductal adenocarcinoma (PDAC). However, it remains unclear whether changes in body composition provide an incremental prognostic value to established risk factors, especially the Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). The aim of this study was to determine the prognostic value of CT-quantified body composition changes in patients with unresectable PDAC starting chemotherapy. METHODS We retrospectively evaluated 105 patients with unresectable (locally advanced or metastatic) PDAC treated with FOLFIRINOX (n = 64) or gemcitabine-based (n = 41) first-line chemotherapy within a multicenter prospective trial. Changes (Δ) in skeletal muscle index (SMI), subcutaneous (SATI), and visceral adipose tissue index (VATI) between pre-chemotherapy and first follow-up CT were assessed. Cox regression models and covariate-adjusted survival curves were used to identify predictors of overall survival (OS). RESULTS At multivariable analysis, adjusting for RECISTv1.1-response at first follow-up, ΔSMI was prognostic for OS with a hazard ratio (HR) of 1.2 (95% CI: 1.08-1.33, p = 0.001). No significant association with OS was observed for ΔSATI (HR: 1, 95% CI: 0.97-1.04, p = 0.88) and ΔVATI (HR: 1.01, 95% CI: 0.99-1.04, p = 0.33). At an optimal cutoff of 2.8 cm2/m2 per 30 days, the median survival of patients with high versus low ΔSMI was 143 versus 233 days (p < 0.001). CONCLUSIONS Patients with a lower rate of skeletal muscle loss at first follow-up demonstrated improved survival for unresectable PDAC, regardless of their RECISTv1.1-category. Assessing ΔSMI at the first follow-up CT may be useful for prognostication, in addition to routine radiological assessment. KEY POINTS • In patients with unresectable pancreatic ductal adenocarcinoma, change of skeletal muscle index (ΔSMI) in the early phase of chemotherapy is prognostic for overall survival, even after adjusting for Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) assessment at first follow-up. • Changes in adipose tissue compartments at first follow-up demonstrated no significant association with overall survival. • Integrating ΔSMI into routine radiological assessment may improve prognostic stratification and impact treatment decision-making at the first follow-up.
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Affiliation(s)
- Emmanuel Salinas-Miranda
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Joint Department of Medical Imaging, University Health Network, Sinai Health System and University of Toronto, Toronto, ON, Canada
| | - Dominik Deniffel
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Joint Department of Medical Imaging, University Health Network, Sinai Health System and University of Toronto, Toronto, ON, Canada.,Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Xin Dong
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Gerard M Healy
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Joint Department of Medical Imaging, University Health Network, Sinai Health System and University of Toronto, Toronto, ON, Canada
| | - Farzad Khalvati
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.,Joint Department of Medical Imaging, University Health Network, Sinai Health System and University of Toronto, Toronto, ON, Canada
| | - Grainne M O'Kane
- Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.,Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Jennifer Knox
- Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada.,Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Oliver F Bathe
- Departments of Surgery and Oncology, University of Calgary, Calgary, AB, Canada
| | - Vickie E Baracos
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
| | - Steven Gallinger
- Ontario Institute for Cancer Research, Toronto, ON, Canada.,Hepatobiliary Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada
| | - Masoom A Haider
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. .,Joint Department of Medical Imaging, University Health Network, Sinai Health System and University of Toronto, Toronto, ON, Canada. .,Ontario Institute for Cancer Research, Toronto, ON, Canada.
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Impact of Artificial Nutrition on Postoperative Complications. Healthcare (Basel) 2020; 8:healthcare8040559. [PMID: 33327483 PMCID: PMC7764968 DOI: 10.3390/healthcare8040559] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/26/2022] Open
Abstract
Malnutrition is common in surgical cancer patients and it is widely accepted that it can adversely affect their postoperative outcome. Assessing the nutritional status of every patient, in particular care of elderly and cancer patients, is a crucial feature of the therapeutic pathway in order to optimize every strategy. Evidence exists that the advantages of perioperative nutrition are more significant in malnourished patients submitted to major surgery. For patients recognized as malnourished, preoperative nutrition therapies are indicated; the choice between parenteral and enteral nutrition is still controversial in perioperative malnourished surgical cancer patients, although enteral nutrition seems to have the best risk–benefit ratio. Early oral nutrition after surgery is advisable, when feasible, and should be administered in all the patients undergoing elective major surgery, if compliant. In patients with high risk for postoperative infections, perioperative immunonutrition has been proved in some ways to be effective, even if operations including those for cancer have to be delayed.
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31
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Sarcopenia: looking to muscle mass to better manage pancreatic cancer patients. Curr Opin Support Palliat Care 2020; 13:279-285. [PMID: 31361630 DOI: 10.1097/spc.0000000000000455] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Overall survival of patients with pancreatic cancer is strongly conditioned by tumor biology and the incidence of malnutrition and metabolic disorders. In this landscape, the assessment of body composition is crucial to properly manage the clinical implications of muscle wasting. The pathogenesis of this condition is the result of a complex interplay between cancer and the host. In particular, sarcopenia is induced by an inadequate nutritional intake, hormonal abnormalities, inflammation and imbalance between anabolic and catabolic pathways. RECENT FINDINGS Recent evidences have highlighted the role of sarcopenia in cancer patients, revealing a prognostic impact on morbidity, mortality and survival. SUMMARY The occurrence of sarcopenia could amplify chemotherapy-induced toxicities, prolong hospitalizations and reduce adherence to anticancer treatment, worsening quality of life and survival. Although considerable efforts have been made to develop treatment strategies, no effective interventions have been identified so far. Nevertheless, if promptly and adequately supported, pancreatic cancer might benefit from adopted dietary intervention to avoid further loss of lean mass.
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Khurana N, Dodhiawala PB, Bulle A, Lim KH. Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12092675. [PMID: 32961746 PMCID: PMC7564842 DOI: 10.3390/cancers12092675] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic inflammation is a major mechanism that underlies the aggressive nature and treatment resistance of pancreatic cancer. In many ways, the molecular mechanisms that drive chronic inflammation in pancreatic cancer are very similar to our body’s normal innate immune response to injury or invading microorganisms. Therefore, during cancer development, pancreatic cancer cells hijack the innate immune pathway to foster a chronically inflamed tumor environment that helps shield them from immune attack and therapeutics. While blocking the innate immune pathway is theoretically reasonable, untoward side effects must also be addressed. In this review, we comprehensively summarize the literature that describe the role of innate immune signaling in pancreatic cancer, emphasizing the specific role of this pathway in different cell types. We review the interaction of the innate immune pathway and cancer-driving signaling in pancreatic cancer and provide an updated overview of novel therapeutic opportunities against this mechanism. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies.
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Affiliation(s)
- Namrata Khurana
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Paarth B Dodhiawala
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ashenafi Bulle
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kian-Huat Lim
- Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
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Liao W, Chen P, Huang C, Chang Y, Huang B, Chang C, Wu M, Chow L. Relationship between pancreatic cancer-associated diabetes and cachexia. J Cachexia Sarcopenia Muscle 2020; 11:899-908. [PMID: 32100478 PMCID: PMC7432579 DOI: 10.1002/jcsm.12553] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/22/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Pancreatic cancer-associated diabetes mellitus (PCDM) is a paraneoplastic phenomenon characterized by worsening hyperglycaemia and weight loss. Galectin-3 and S100A9, mediators of PCDM, have pro-inflammatory functions and might thereby induce systemic inflammation and cachexia. We aimed to examine whether PCDM directly mediates cachexia. METHODS Consecutive pancreatic cancer (PC) patients with and without PCDM (n = 88 each) with complete information were included. Cachexia was defined as weight loss >5% within 6 months or weight loss >2% and body mass index <20 kg/m2 or sarcopenia. Skeletal muscle mass was measured with lumbar skeletal muscle index (SMI) using computed tomography images. Cachexia-related parameters (prevalence of cachexia, weight loss, and SMI) were compared between patients with and without PCDM. Relations between cachexia-related parameters and fasting blood glucose or serum levels of galectin-3 and S100A9 were analysed by Spearman correlation and logistic regression analyses. RESULTS One hundred two (58.0%) patients had cachexia at diagnosis. No significant differences existed between patients with and without PCDM in prevalence of cachexia (64.8% vs. 51.1%, P = 0.093), percentage of weight loss (median 6.8 vs. 4.0, P = 0.085), and SMI (median 45.8 vs. 45.3 cm2 /m2 in men, P = 0.119; 34.9 vs. 36.3 cm2 /m2 in women, P = 0.418). In patients with cachexia, the percentage of weight loss and SMI were also similar between patients with and without PCDM. In patients with PCDM, fasting blood glucose was comparable between patients with and without cachexia (P = 0.458) and did not correlate with the percentage of weight loss (P = 0.085) or SMI (P = 0.797 in men and 0.679 in women). Serum S100A9 level correlated with fasting blood glucose (correlation coefficient 0.213, P = 0.047) but not with the percentage of weight loss (P = 0.977) or SMI (P = 0.247 in men and 0.458 in women). Serum galectin-3 level also did not correlate with the percentage of weight loss (P = 0.226) and SMI (P = 0.201 in men and 0.826 in women). Primary tumour size was associated with cachexia (adjusted odds ratio per 1 cm increase 1.28, 95% confidence interval 1.02-1.60, P = 0.034), whereas PCDM, fasting blood glucose, and levels of galectin-3 and S100A9 were not predictors of cachexia. CONCLUSIONS Neither fasting blood glucose nor levels of galectin-3 and S100A9 were associated with cachexia-related parameters. Mediators of PCDM and hyperglycaemia do not directly mediate PC-induced cachexia.
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Affiliation(s)
- Wei‐Chih Liao
- Division of Gastroenterology and Hepatology, Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Internal Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Peng‐Ruei Chen
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Cheng‐Chieh Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Yen‐Tzu Chang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Bo‐Shih Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Chin‐Chen Chang
- Department of Medical ImagingNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Department and Graduate Institute of Forensic MedicineNational Taiwan University College of MedicineTaipeiTaiwan
| | - Ming‐Shiang Wu
- Division of Gastroenterology and Hepatology, Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Internal Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Lu‐Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
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Zhang QB, Ye RF, Ye LY, Zhang QY, Dai NG. Isocorydine decrease gemcitabine-resistance by inhibiting epithelial-mesenchymal transition via STAT3 in pancreatic cancer cells. Am J Transl Res 2020; 12:3702-3714. [PMID: 32774728 PMCID: PMC7407734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 06/04/2020] [Indexed: 06/11/2023]
Abstract
Gemcitabine is widely used as an anticancer chemotherapy drug for a variety of solid tumors, and it has become the standard treatment option for locally advanced and metastatic pancreatic cancer. However, pancreatic cancer cells develop resistance to gemcitabine after a few weeks of treatment, resulting in poor therapeutic effects. Isocorydine (ICD) is a typical natural aporphine alkaloid, and ICD and its derivatives inhibit the proliferation of many types of cancer cells in vitro. In this study, ICD was found to synergistically inhibit cell viability with gemcitabine in pancreatic cancer cells. A microarray analysis showed that ICD can inhibit the upregulation of STAT3 and EMT in pancreatic cancer cells induced by gemcitabine. STAT3 is closely related to tumor EMT, migration and invasion. After knocking down the expression of STAT3 in pancreatic cancer cells, the combination index (CI) of ICD and gemcitabine decreased. ICD can reverse the increase in the expression of EMT-related transcription factors and proteins caused by gemcitabine, thereby inhibiting the enhanced cell migration and invasion ability caused by gemcitabine. Finally, the synergistic treatment effect of the combination treatment of ICD and gemcitabine in pancreatic cancer cells was confirmed in established xenograft models.
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Affiliation(s)
- Quan-Bo Zhang
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Rui-Fan Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Long-Yun Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Qi-Yu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
| | - Ning-Gao Dai
- Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou, China
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Poulia KA, Sarantis P, Antoniadou D, Koustas E, Papadimitropoulou A, Papavassiliou AG, Karamouzis MV. Pancreatic Cancer and Cachexia-Metabolic Mechanisms and Novel Insights. Nutrients 2020; 12:E1543. [PMID: 32466362 PMCID: PMC7352917 DOI: 10.3390/nu12061543] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 05/15/2020] [Accepted: 05/25/2020] [Indexed: 02/06/2023] Open
Abstract
Cachexia is a major characteristic of multiple non-malignant diseases, advanced and metastatic cancers and it is highly prevalent in pancreatic cancer, affecting almost 70-80% of the patients. Cancer cachexia is a multifactorial condition accompanied by compromised appetite and changes in body composition, i.e., loss of fat. It is associated with lower effectiveness of treatment, compromised quality of life, and higher mortality. Understanding the complex pathways underlying the pathophysiology of cancer cachexia, new therapeutic targets will be unraveled. The interplay between tumor and host factors, such as cytokines, holds a central role in cachexia pathophysiology. Cytokines are possibly responsible for anorexia, hypermetabolism, muscle proteolysis, and apoptosis. In particular, cachexia in pancreatic cancer might be the result of the surgical removal of pancreas parts. In recent years, many studies have been carried out to identify an effective treatment algorithm for cachexia. Choosing the most appropriate treatment, the clinical effect and the risk of adverse effects should be taken under consideration. The purpose of this review is to highlight the pathophysiological mechanisms as well as the current ways of cachexia treatment in the pharmaceutical and the nutrition field.
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Affiliation(s)
- Kalliopi Anna Poulia
- Department of Nutrition and Dietetics, Laiko General Hospital, 11527 Athens, Greece;
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (E.K.); (A.G.P.)
| | - Dimitra Antoniadou
- Oncology Department of Daily Hospitality, Laiko General Hospital, 11527 Athens, Greece;
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (E.K.); (A.G.P.)
| | - Adriana Papadimitropoulou
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (E.K.); (A.G.P.)
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.S.); (E.K.); (A.G.P.)
- First Department of Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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Shukla SK, Markov SD, Attri KS, Vernucci E, King RJ, Dasgupta A, Grandgenett PM, Hollingsworth MA, Singh PK, Yu F, Mehla K. Macrophages potentiate STAT3 signaling in skeletal muscles and regulate pancreatic cancer cachexia. Cancer Lett 2020; 484:29-39. [PMID: 32344015 DOI: 10.1016/j.canlet.2020.04.017] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/06/2020] [Accepted: 04/20/2020] [Indexed: 12/25/2022]
Abstract
Incidence of cachexia is highly prevalent in pancreatic ductal adenocarcinoma (PDAC); advanced disease stage directly correlates with decreased muscle and fat mass in PDAC patients. The pancreatic tumor microenvironment is central to the release of systemic factors that govern lipolysis, proteolysis, and muscle and fat degeneration leading to the cachectic phenotype in cancer patients. The current study explores the role of macrophages, a key immunosuppressive player in the pancreatic tumor microenvironment, in regulating cancer cachexia. We observed a negative correlation between CD163-positive macrophage infiltration and muscle-fiber cross sectional area in human PDAC patients. To investigate the role of macrophages in myodegeneration, we utilized conditioned media transplant assays and orthotopic models of PDAC-induced cachexia in immune-competent mice with and without macrophage depletion. We observed that macrophage-derived conditioned medium, in combination with tumor cell-conditioned medium, promoted muscle atrophy through STAT3 signaling. Furthermore, macrophage depletion attenuated systemic inflammation and muscle wasting in pancreatic tumor-bearing mice. Targeting macrophage-mediated STAT3 activation or macrophage-derived interleukin-1 alpha or interleukin-6 diminished myofiber atrophy. Taken together, the current study identified the critical association between macrophages and cachexia phenotype in pancreatic cancer.
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Affiliation(s)
- Surendra K Shukla
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Spas D Markov
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kuldeep S Attri
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Enza Vernucci
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ryan J King
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Aneesha Dasgupta
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paul M Grandgenett
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Michael A Hollingsworth
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pankaj K Singh
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Fang Yu
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kamiya Mehla
- The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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Görgülü K, Diakopoulos KN, Kaya-Aksoy E, Ciecielski KJ, Ai J, Lesina M, Algül H. The Role of Autophagy in Pancreatic Cancer: From Bench to the Dark Bedside. Cells 2020; 9:E1063. [PMID: 32344698 PMCID: PMC7226443 DOI: 10.3390/cells9041063] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 02/27/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is one of the deadliest cancer types urgently requiring effective therapeutic strategies. Autophagy occurs in several compartments of pancreatic cancer tissue including cancer cells, cancer associated fibroblasts, and immune cells where it can be subjected to a multitude of stimulatory and inhibitory signals fine-tuning its activity. Therefore, the effects of autophagy on pancreatic carcinogenesis and progression differ in a stage and context dependent manner. In the initiation stage autophagy hinders development of preneoplastic lesions; in the progression stage however, autophagy promotes tumor growth. This double-edged action of autophagy makes it a hard therapeutic target. Indeed, autophagy inhibitors have not yet shown survival improvements in clinical trials, indicating a need for better evaluation of existing results and smarter targeting techniques. Clearly, the role of autophagy in pancreatic cancer is complex and many aspects have to be considered when moving from the bench to the bedside.
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Affiliation(s)
- Kıvanç Görgülü
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Kalliope N. Diakopoulos
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Ezgi Kaya-Aksoy
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Katrin J. Ciecielski
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Jiaoyu Ai
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Marina Lesina
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
| | - Hana Algül
- Comprehensive Cancer Center Munich, Technische Universität München, 81675 Munich, Germany; (K.N.D.); (E.K.-A.); (K.J.C.); (J.A.); (M.L.)
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Zhong X, Pons M, Poirier C, Jiang Y, Liu J, Sandusky GE, Shahda S, Nakeeb A, Schmidt CM, House MG, Ceppa EP, Zyromski NJ, Liu Y, Jiang G, Couch ME, Koniaris LG, Zimmers TA. The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy. J Cachexia Sarcopenia Muscle 2019; 10:1083-1101. [PMID: 31286691 PMCID: PMC6818463 DOI: 10.1002/jcsm.12461] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 04/19/2019] [Accepted: 05/14/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. METHODS Isoform-specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed-forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. RESULTS Murine PDAC tumour-derived cell lines expressed activin-βA but not activin-βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin-low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin-high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin-βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. CONCLUSIONS Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ-specific and gene-specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle-specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene-specific and organ-specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.
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Affiliation(s)
- Xiaoling Zhong
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IUPUI Center for Cachexia Innovation, Research and TherapyIndianapolisINUSA
| | - Marianne Pons
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - Christophe Poirier
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - Yanlin Jiang
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - Jianguo Liu
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - George E. Sandusky
- Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
| | - Safi Shahda
- IU Simon Cancer CenterIndianapolisINUSA
- Department of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Attila Nakeeb
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
| | - C. Max Schmidt
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
| | - Michael G. House
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
| | - Eugene P. Ceppa
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
| | - Nicholas J. Zyromski
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
| | - Yunlong Liu
- IUPUI Center for Cachexia Innovation, Research and TherapyIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
- Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisINUSA
- Center for Computational Biology and BioinformaticsIndiana University School of MedicineIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndiana University School of MedicineIndianapolisINUSA
| | - Guanglong Jiang
- Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisINUSA
| | - Marion E. Couch
- IU Simon Cancer CenterIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndiana University School of MedicineIndianapolisINUSA
- Department of Otolaryngology—Head & Neck SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - Leonidas G. Koniaris
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IUPUI Center for Cachexia Innovation, Research and TherapyIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndiana University School of MedicineIndianapolisINUSA
| | - Teresa A. Zimmers
- Department of SurgeryIndiana University School of MedicineIndianapolisINUSA
- IUPUI Center for Cachexia Innovation, Research and TherapyIndianapolisINUSA
- IU Simon Cancer CenterIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndiana University School of MedicineIndianapolisINUSA
- Department of Otolaryngology—Head & Neck SurgeryIndiana University School of MedicineIndianapolisINUSA
- Department of Anatomy, Cell Biology & PhysiologyIndiana University School of MedicineIndianapolisINUSA
- Department of Biochemistry and Molecular BiologyIndiana University School of MedicineIndianapolisINUSA
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39
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Babic A, Rosenthal MH, Bamlet WR, Takahashi N, Sugimoto M, Danai LV, Morales-Oyarvide V, Khalaf N, Dunne RF, Brais LK, Welch MW, Zellers CL, Dennis C, Rifai N, Prado CM, Caan B, Sundaresan TK, Meyerhardt JA, Kulke MH, Clish CB, Ng K, Vander Heiden MG, Petersen GM, Wolpin BM. Postdiagnosis Loss of Skeletal Muscle, but Not Adipose Tissue, Is Associated with Shorter Survival of Patients with Advanced Pancreatic Cancer. Cancer Epidemiol Biomarkers Prev 2019; 28:2062-2069. [PMID: 31533940 DOI: 10.1158/1055-9965.epi-19-0370] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 05/29/2019] [Accepted: 08/27/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Pancreatic cancer is associated with development of cachexia, a wasting syndrome thought to limit survival. Few studies have longitudinally quantified peripheral tissues or identified biomarkers predictive of future tissue wasting. METHODS Adipose and muscle tissue were measured by computed tomography (CT) at diagnosis and 50 to 120 days later in 164 patients with advanced pancreatic cancer. Tissue changes and survival were evaluated by Cox proportional hazards regression. Baseline levels of circulating markers were examined in relation to future tissue wasting. RESULTS Compared with patients in the bottom quartile of muscle change per 30 days (average gain of 0.8 ± 2.0 cm2), those in the top quartile (average loss of 12.9 ± 4.9 cm2) had a hazard ratio (HR) for death of 2.01 [95% confidence interval (CI), 1.12-3.62]. Patients in the top quartile of muscle attenuation change (average decrease of 4.9 ± 2.4 Hounsfield units) had an HR of 2.19 (95% CI, 1.18-4.04) compared with those in the bottom quartile (average increase of 2.4 ± 1.6 Hounsfield units). Changes in adipose tissue were not associated with survival. Higher plasma branched chain amino acids (BCAA; P = 0.004) and lower monocyte chemoattractant protein-1 (MCP-1; P = 0.005) at diagnosis were associated with greater future muscle loss. CONCLUSIONS In patients with advanced pancreatic cancer, muscle loss and decrease in muscle density in 2 to 4 months after diagnosis were associated with reduced survival. BCAAs and MCP-1 levels at diagnosis were associated with subsequent muscle loss. IMPACT BCAAs and MCP-1 levels at diagnosis could identify a high-risk group for future tissue wasting.
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Affiliation(s)
- Ana Babic
- Dana-Farber Cancer Institute, Boston, Massachusetts.
| | - Michael H Rosenthal
- Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts
| | | | | | | | - Laura V Danai
- Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, Massachusetts
| | | | - Natalia Khalaf
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts
| | - Richard F Dunne
- Division of Hematology/Oncology, University of Rochester Medical Center, Rochester, New York
| | | | | | | | - Courtney Dennis
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts
| | - Nader Rifai
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts
| | - Carla M Prado
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
| | - Bette Caan
- Kaiser Permanente Division of Research, Oakland, California
| | | | | | - Matthew H Kulke
- Dana-Farber Cancer Institute, Boston, Massachusetts.,Boston University and Boston Medical Center, Section of Hematology/Oncology, Boston, Massachusetts
| | - Clary B Clish
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts
| | - Kimmie Ng
- Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Matthew G Vander Heiden
- Dana-Farber Cancer Institute, Boston, Massachusetts.,Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
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40
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Liu J, Huang Y, Liu Y, Chen Y. Irisin Enhances Doxorubicin-Induced Cell Apoptosis in Pancreatic Cancer by Inhibiting the PI3K/AKT/NF-κB Pathway. Med Sci Monit 2019; 25:6085-6096. [PMID: 31412018 PMCID: PMC6705179 DOI: 10.12659/msm.917625] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background Irisin, a myokine released from skeletal muscle following exercise, has been shown to affect the proliferation of some cancer cells and chemosensitivity of anticancer drugs like doxorubicin (DOX). However, the effects of irisin on chemosensitivity in pancreatic cancer (PC) cells have not been studied. Material/Methods In this study, the effects of irisin co-treatment with DOX or gemcitabine (GEM) on MIA PaCa-2, BxPC-3 PC cells, and H9c2 cardiomyocytes were investigated. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, flow cytometry, and TUNEL (TdT-mediated dUTP nick-end labeling) assays were conducted to evaluate cytotoxicity induced by DOX or GEM. Fluorescence microscopy and flow cytometry experiments were performed to assess the intracellular accumulation of DOX. Cellular levels of apoptosis-related protein expression and protein phosphorylation were determined by Western blot analyses. Results The results showed that irisin can increase the chemosensitivity of PC cells to DOX or GEM. The analyses of apoptosis indicated that irisin enhances DOX-induced cellular apoptosis by increasing the expression of cleaved PARP (poly ADP-ribose polymerase) and cleaved caspase-3, and reducing the expression of B cell lymphoma/lewkmia-2 (BCL-2) and B cell lymphoma-extra large (BCL-xL) in PC cells but not in H9c2 cells. Irisin attenuated serine/threonine kinase AKT (protein kinase B/PKB) phosphorylation and inhibited the activation of nuclear factor κB (NF-κB) signaling in PC cells. Conclusions Irisin can potentiate the cytotoxicity of doxorubicin in PC cells without increasing cardiotoxicity, possibly through inactivating the PI3K/AKT/NF-κB signaling pathway.
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Affiliation(s)
- Jiayu Liu
- Key Laboratory for Molecular Enzymology and Engineering of The Ministry of Education, Jilin University, Changchun, Jilin, China (mainland).,School of Life Sciences, Jilin University, Changchun, Jilin, China (mainland)
| | - Yibing Huang
- Key Laboratory for Molecular Enzymology and Engineering of The Ministry of Education, Jilin University, Changchun, Jilin, China (mainland).,School of Life Sciences, Jilin University, Changchun, Jilin, China (mainland)
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Yuxin Chen
- Key Laboratory for Molecular Enzymology and Engineering of The Ministry of Education, Jilin University, Changchun, Jilin, China (mainland).,School of Life Sciences, Jilin University, Changchun, Jilin, China (mainland)
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41
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Permuth JB, Clark Daly A, Jeong D, Choi JW, Cameron ME, Chen D, Teer JK, Barnett TE, Li J, Powers BD, Kumar NB, George TJ, Ali KN, Huynh T, Vyas S, Gwede CK, Simmons VN, Hodul PJ, Carballido EM, Judge AR, Fleming JB, Merchant N, Trevino JG. Racial and ethnic disparities in a state-wide registry of patients with pancreatic cancer and an exploratory investigation of cancer cachexia as a contributor to observed inequities. Cancer Med 2019; 8:3314-3324. [PMID: 31074202 PMCID: PMC6558500 DOI: 10.1002/cam4.2180] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/29/2019] [Accepted: 04/03/2019] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer (PC) is characterized by racial/ethnic disparities and the debilitating muscle-wasting condition, cancer cachexia. Florida ranks second in the number of PC deaths and has a large and understudied minority population. We examined the primary hypothesis that PC incidence and mortality rates may be highest among Black Floridians and the secondary hypothesis that biological correlates of cancer cachexia may underlie disparities. PC incidence and mortality rates were estimated by race/ethnicity, gender, and county using publicly available state-wide cancer registry data that included approximately 2700 Black, 25 200 Non-Hispanic White (NHW), and 3300 Hispanic/Latino (H/L) Floridians diagnosed between 2004 and 2014. Blacks within Florida experienced a significantly (P < 0.05) higher incidence (12.5/100 000) and mortality (10.97/100 000) compared to NHW (incidence = 11.2/100 000; mortality = 10.3/100 000) and H/L (incidence = 9.6/100 000; mortality = 8.7/100 000), especially in rural counties. To investigate radiologic and blood-based correlates of cachexia, we leveraged data from a subset of patients evaluated at two geographically distinct Florida Cancer Centers. In Blacks compared to NHW matched on stage, markers of PC-induced cachexia were more frequent and included greater decreases in core musculature compared to corresponding healthy control patients (25.0% vs 10.1% lower), greater decreases in psoas musculature over time (10.5% vs 4.8% loss), lower baseline serum albumin levels (3.8 vs 4.0 gm/dL), and higher platelet counts (332.8 vs 268.7 k/UL). Together, these findings suggest for the first time that PC and cachexia may affect Blacks disproportionately. Given its nearly universal contribution to illness and PC-related deaths, the early diagnosis and treatment of cachexia may represent an avenue to improve health equity, quality of life, and survival.
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Affiliation(s)
- Jennifer B. Permuth
- Department of Cancer EpidemiologyMoffitt Cancer CenterTampaFlorida
- Department of Gastrointestinal OncologyMoffitt Cancer CenterTampaFlorida
| | - Ashley Clark Daly
- Division of Behavioral HealthIdaho Department of Health and WelfareBoiseIdaho
| | - Daniel Jeong
- Department of Diagnostic RadiologyMoffitt Cancer CenterTampaFlorida
| | - Jung W. Choi
- Department of Cancer Imaging & MetabolismMoffitt Cancer CenterTampaFlorida
| | - Miles E. Cameron
- Department of Surgery, Division of General SurgeryUniversity of Florida Health Sciences CenterGainesvilleFlorida
| | - Dung‐Tsa Chen
- Department of Biostatistics and BioinformaticsMoffitt Cancer CenterTampaFlorida
| | - Jamie K. Teer
- Department of Biostatistics and BioinformaticsMoffitt Cancer CenterTampaFlorida
| | - Tracey E. Barnett
- School of Public HealthUniversity of North Texas Health Science CenterFort WorthTexas
| | - Jiannong Li
- Department of Biostatistics and BioinformaticsMoffitt Cancer CenterTampaFlorida
| | - Benjamin D. Powers
- Department of Gastrointestinal OncologyMoffitt Cancer CenterTampaFlorida
| | | | - Thomas J. George
- Department of MedicineUniversity of Florida Health Sciences CenterGainesvilleFlorida
| | - Karla N. Ali
- Department of Cancer EpidemiologyMoffitt Cancer CenterTampaFlorida
| | - Tri Huynh
- Department of Cancer EpidemiologyMoffitt Cancer CenterTampaFlorida
| | - Shraddha Vyas
- Department of Cancer EpidemiologyMoffitt Cancer CenterTampaFlorida
| | - Clement K. Gwede
- Department of Health Outcomes and BehaviorMoffitt Cancer CenterTampaFlorida
| | - Vani N. Simmons
- Department of Health Outcomes and BehaviorMoffitt Cancer CenterTampaFlorida
| | - Pamela J. Hodul
- Department of Gastrointestinal OncologyMoffitt Cancer CenterTampaFlorida
| | | | - Andrew R. Judge
- Department of Physical TherapyUniversity of FloridaGainesvilleFlorida
| | - Jason B. Fleming
- Department of Gastrointestinal OncologyMoffitt Cancer CenterTampaFlorida
| | - Nipun Merchant
- Department of Surgical Oncology, Sylvester Comprehensive Cancer CenterUniversity of Miami Miller School of MedicineMiamiFlorida
| | - Jose G. Trevino
- Department of Surgery, Division of General SurgeryUniversity of Florida Health Sciences CenterGainesvilleFlorida
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42
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Gruber ES, Jomrich G, Tamandl D, Gnant M, Schindl M, Sahora K. Sarcopenia and sarcopenic obesity are independent adverse prognostic factors in resectable pancreatic ductal adenocarcinoma. PLoS One 2019; 14:e0215915. [PMID: 31059520 PMCID: PMC6502449 DOI: 10.1371/journal.pone.0215915] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 04/10/2019] [Indexed: 02/07/2023] Open
Abstract
Background Incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are on the rise. Sarcopenia and sarcopenic obesity have proven to be prognostic factors in different types of cancers. In the context of previous findings, we evaluated the impact of body composition in patients undergoing surgery in a national pancreatic center. Methods Patient’s body composition (n = 133) was analyzed on diagnostic CT scans and defined as follows: Skeletal muscle index ≤38.5 cm2/m2 (women), ≤52.4 cm2/m2 (men); obesity was classified as BMI ≥25kg/m2. Results Sarcopenia showed a negative impact on overall survival (OS; 14 vs. 20 months, p = 0.016). Sarcopenic patients suffering from obesity showed poorer OS compared to non-sarcopenic obese patients (14 vs. 23 months, p = 0.007). Both sarcopenia and sarcopenic obesity were associated with sex (p<0.001 and p = 0.006; males vs. females 20% vs. 38% and 12% vs. 38%, respectively); sarcopenia was further associated with neoadjuvant treatment (p = 0.025), tumor grade (p = 0.023), weight loss (p = 0.02) and nutritional depletion (albumin, p = 0.011) as well as low BMI (<25 kg/m2, p = 0.038). Sarcopenic obese patients showed higher incidence of major postoperative complications (p<0.001). In addition, sarcopenia proved as an independent prognostic factor for OS (p = 0.031) in the multivariable Cox Regression model. Conclusion Patients with sarcopenia and sarcopenic obesity undergoing resection for PDAC have a significantly shorter overall survival and a higher complication rate. The assessment of body composition in these patients may provide a broader understanding of patients’ individual condition and guide specific supportive strategies in patients at risk.
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Affiliation(s)
- Elisabeth S. Gruber
- Division of General Surgery, Department of Surgery, Pancreatic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- * E-mail: (ESG); (KS)
| | - Gerd Jomrich
- Division of General Surgery, Department of Surgery, Pancreatic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Dietmar Tamandl
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Michael Gnant
- Division of General Surgery, Department of Surgery, Pancreatic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Martin Schindl
- Division of General Surgery, Department of Surgery, Pancreatic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Klaus Sahora
- Division of General Surgery, Department of Surgery, Pancreatic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- * E-mail: (ESG); (KS)
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Hendifar AE, Petzel MQB, Zimmers TA, Denlinger CS, Matrisian LM, Picozzi VJ, Rahib L. Pancreas Cancer-Associated Weight Loss. Oncologist 2019; 24:691-701. [PMID: 30591550 PMCID: PMC6516128 DOI: 10.1634/theoncologist.2018-0266] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 10/18/2018] [Indexed: 12/17/2022] Open
Abstract
Unintentional weight loss in patients with pancreatic cancer is highly prevalent and contributes to low therapeutic tolerance, reduced quality of life, and overall mortality. Weight loss in pancreatic cancer can be due to anorexia, malabsorption, and/or cachexia. Proper supportive care can stabilize or reverse weight loss in patients and improve outcomes. We review the literature on supportive care relevant to pancreatic cancer patients, and offer evidence-based recommendations that include expert nutritional assessment, counseling, supportive measures to ensure adequate caloric intake, pancreatic enzyme supplementation, nutritional supplement replacement, orexigenic agents, and exercise. Pancreatic Cancer Action Network-supported initiatives will spearhead the dissemination and adoption of these best supportive care practices. IMPLICATIONS FOR PRACTICE: Weight loss in pancreatic cancer patients is endemic, as 85% of pancreatic cancer patients meet the classic definition of cancer cachexia. Despite its significant prevalence and associated morbidity, there is no established approach to this disease entity. It is believed that this is due to an important knowledge gap in understanding the underlying biology and lack of optimal treatment approaches. This article reviews the literature regarding pancreas cancer-associated weight loss and establishes a new framework from which to view this complex clinical problem. An improved approach and understanding will help educate clinicians, improve clinical care, and provide more clarity for future clinical investigation.
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Affiliation(s)
| | | | - Teresa A Zimmers
- Indiana University, Simon Cancer Center, Indianapolis, Indiana, USA
| | | | - Lynn M Matrisian
- Pancreatic Cancer Action Network, Manhattan Beach, California, USA
| | | | - Lola Rahib
- Pancreatic Cancer Action Network, Manhattan Beach, California, USA
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44
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Jang M, Park HW, Huh J, Lee JH, Jeong YK, Nah YW, Park J, Kim KW. Predictive value of sarcopenia and visceral obesity for postoperative pancreatic fistula after pancreaticoduodenectomy analyzed on clinically acquired CT and MRI. Eur Radiol 2019; 29:2417-2425. [PMID: 30406311 DOI: 10.1007/s00330-018-5790-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 09/06/2018] [Accepted: 09/21/2018] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To evaluate predictive values of sarcopenia and visceral obesity measured from preoperative CT/MRIs for postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy in patients with periampullary malignancies. METHODS From the prospectively constructed surgical registry, we included adult patients treated with pancreaticoduodenectomy. Based on CT/MRIs, body morphometric analysis was performed to evaluate the visceral obesity and sarcopenia, based on the areas of visceral fat and skeletal muscle measured at the L3 vertebrae level. We retrieved various perioperative factors from registry. As outcomes of postoperative complications, we evaluated POPF and major complications based on the Clavien-Dindo classification. Multivariate logistic regression analyses were performed. RESULTS From a total of 284 patients (163 males, 121 females) who met the inclusion/exclusion criteria, POPF, major complications, and 60-day mortality occurred in 52 (18.3%), 34 (12.0%), and 6 (2.1%), respectively. Sarcopenia and visceral obesity were noted in 123 (75.5%) and 66 (40.5%) of men and 68 (56.2%) and 53 (43.8%) of women, respectively. Combination of sarcopenia and obesity (sarcopenic obesity) was noted in 31.9% (52/163) of men and in 26.4% (32/121) of women. In multivariate logistic regression analyses, sarcopenic obesity was the only independent predictor for POPF (OR 2.65, 95% CI 1.43-4.93), and the vascular resection during pancreaticoduodenectomy was the only independent predictor for severe complications (OR 3.75, 95% CI 1.61-8.70). CONCLUSION Sarcopenic obesity might be highly predictive for POPF. Body morphometric analysis in preoperative CT/MRI combined with assessment of perioperative clinical features may help to identify high-risk patients and determine perioperative management strategies. KEY POINTS • Sarcopenic obesity might be predictive for postoperative pancreatic fistula after pancreaticoduodenectomy. • The vascular resection during pancreaticoduodenectomy might be predictive of major complications. • Body morphometric analysis might be helpful for identifying high-risk patients.
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Affiliation(s)
- Minji Jang
- Department of Radiology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea
| | - Hyung Woo Park
- Department of Surgery, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea
| | - Jimi Huh
- Department of Radiology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea.
- Department of Radiology, Ajou University School of Medicine & Graduate School of Medicine, Ajou University Medical Center, 164 World cup-ro, Yeongtong-gu, Suwon, 16499, South Korea.
| | - Jong Hwa Lee
- Department of Radiology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea
| | - Yoong Ki Jeong
- Department of Radiology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea
| | - Yang Won Nah
- Department of Surgery, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea
| | - Jisuk Park
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Kyung Won Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
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45
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Zhu X, Burfeind KG, Michaelis KA, Braun TP, Olson B, Pelz KR, Morgan TK, Marks DL. MyD88 signalling is critical in the development of pancreatic cancer cachexia. J Cachexia Sarcopenia Muscle 2019; 10:378-390. [PMID: 30666818 PMCID: PMC6463469 DOI: 10.1002/jcsm.12377] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 11/08/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Up to 80% of pancreatic cancer patients suffer from cachexia, a devastating condition that exacerbates underlying disease, reduces quality of life, and increases treatment complications and mortality. Tumour-induced inflammation is linked to this multifactorial wasting syndrome, but mechanisms and effective treatments remain elusive. Myeloid differentiation factor (MyD88), a key component of the innate immune system, plays a pivotal role in directing the inflammatory response to various insults. In this study, we tested whether MyD88 signalling is essential in the development of pancreatic cancer cachexia using a robust mouse tumour model. METHODS Sex, age, and body weight-matched wide type (WT) and MyD88 knockout (MyD88 KO) mice were orthotopically or intraperitoneally implanted with a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D/+ P53R172H/+ Pdx-Cre (KPC) mouse. We observed the effects of MyD88 signalling during pancreatic ductal adenocarcinoma progression and the cachexia development through behavioural, histological, molecular, and survival aspects. RESULTS Blocking MyD88 signalling greatly ameliorated pancreatic ductal adenocarcinoma-associated anorexia and fatigue, attenuated lean mass loss, reduced muscle catabolism and atrophy, diminished systemic and central nervous system inflammation, and ultimately improved survival. Our data demonstrate that MyD88 signalling plays a critical role in mediating pancreatic cancer-induced inflammation that triggers cachexia development and therefore represents a promising therapeutic target. CONCLUSIONS MyD88-dependent inflammation is crucial in the pathophysiology of pancreatic cancer progression and contributes to high mortality. Our findings implicate the importance of innate immune signalling pathways in pancreatic cancer cachexia and a novel therapeutic target.
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Affiliation(s)
- Xinxia Zhu
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Kevin G Burfeind
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, 97239, USA.,Medical Scientist Training Program, Oregon Health & Science University, Portland, USA
| | - Katherine A Michaelis
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, 97239, USA.,Medical Scientist Training Program, Oregon Health & Science University, Portland, USA
| | - Theodore P Braun
- Knight Cancer Institute, Oregon Health & Science University, Portland, USA
| | - Brennan Olson
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, 97239, USA.,Medical Scientist Training Program, Oregon Health & Science University, Portland, USA
| | - Katherine R Pelz
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, 97239, USA
| | - Terry K Morgan
- Department of Pathology, Oregon Health & Science University, Portland, USA
| | - Daniel L Marks
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR, 97239, USA.,Knight Cancer Institute, Oregon Health & Science University, Portland, USA
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46
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Wong HCY, Lam KY, Chong CCN, Chan AWH, Chan SL. Impact of Weight Loss During Chemotherapy in Chinese Patients with Unresectable Pancreatic Cancer. Nutr Cancer 2019; 71:954-970. [PMID: 31058551 DOI: 10.1080/01635581.2019.1595047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Background: Weight loss is frequently observed in pancreatic cancer patients. We aimed to study the prognostic impacts of weight loss early during chemotherapy. Methods: A total of 72 patients of Chinese ethnicity with unresectable pancreatic cancer who underwent chemotherapy were reviewed. Critical weight loss (CWL) was defined as weight loss ≥ 5% within one month after treatment. The prognostic impact of weight loss and CWL were analyzed. Results: 47 patients (65.3%) had weight loss after one month of treatment, with 14 (19.4%) suffering from CWL. Baseline characteristics were similar between patients with and without CWL. The median OS and Time-to-treatment-failure (TTF) of patients with CWL were shorter than those without CWL (OS: 4.8 months [CWL] versus [vs.] OS 7.1 months [No CWL]; TTF 1.6 months [CWL] vs. 3.2 months [No CWL]; both P < 0.01). CWL was an independent adverse prognosticator for OS (Hazard Ratio [HR] = 2.50; P = 0.01) and TTF (HR = 2.71; P < 0.01). Other independent prognosticators for OS were serum albumin <35 mg/dl and CA19-9 ≥ 1000 IU/ml, while CWL was the only independent prognosticator for TTF (HR 2.71 [95% CI 1.33-5.52]; P < 0.01). Conclusions: Development of CWL in early course of chemotherapy was associated with worse prognosis in Chinese patients with unresectable pancreatic cancers.
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Affiliation(s)
- Henry C Y Wong
- a Department of Oncology , Princess Margaret Hospital , Hong Kong
| | - Kwan Y Lam
- b Department of Clinical Oncology , Sir YK Pao Center for Cancer, Prince of Wales Hospital , Hong Kong
| | - Charing C N Chong
- c Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery , The Chinese University of Hong Kong , Hong Kong
| | - Anthony W H Chan
- d Department of Anatomical and Cellular Pathology , Prince of Wales Hospital, The Chinese University of Hong Kong , Hong Kong
- e State Key Laboratory in Oncology in South China , The Chinese University of Hong Kong , Hong Kong
| | - Stephen L Chan
- b Department of Clinical Oncology , Sir YK Pao Center for Cancer, Prince of Wales Hospital , Hong Kong
- e State Key Laboratory in Oncology in South China , The Chinese University of Hong Kong , Hong Kong
- f Institute of Digestive Disease , The Chinese University of Hong Kong , Hong Kong
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47
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Yakovenko A, Cameron M, Trevino JG. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J Gastrointest Surg 2018; 10:95-106. [PMID: 30622678 PMCID: PMC6314860 DOI: 10.4240/wjgs.v10.i9.95] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/01/2018] [Accepted: 11/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) induced cachexia is a complex metabolic syndrome associated with significantly increased morbidity and mortality and reduced quality of life. The pathophysiology of cachexia is complex and poorly understood. Many molecular signaling pathways are involved in PC and cachexia. Though our understanding of cancer cachexia is growing, therapeutic options remain limited. Thus, further discovery and investigation of the molecular signaling pathways involved in the pathophysiology of cachexia can be applied to development of targeted therapies. This review focuses on three main pathophysiologic processes implicated in the development and progression of cachexia in PC, as well as their utility in the discovery of novel targeted therapies.
Skeletal muscle wasting is the most prominent pathophysiologic anomaly in cachectic patients and driven by multiple regulatory pathways. Several known molecular pathways that mediate muscle wasting and cachexia include transforming growth factor-beta (TGF-β), myostatin and activin, IGF-1/PI3K/AKT, and JAK-STAT signaling. TGF-β antagonism in cachectic mice reduces skeletal muscle catabolism and weight loss, while improving overall survival. Myostatin/activin inhibition has a great therapeutic potential since it plays an essential role in skeletal muscle regulation. Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) leads to increased ubiquitination associated proteolysis, inhibition of myogenesis, and decreased muscle mass in PC induced cachexia. IGFBP-3 antagonism alleviates muscle cell wasting.
Another component of cachexia is profound systemic inflammation driven by pro-cachectic cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon gamma (INF-γ). IL-6 antagonism has been shown to reduce inflammation, reduce skeletal muscle loss, and ameliorate cachexia. While TNF-α inhibitors are clinically available, blocking TNF-α signaling is not effective in the treatment of cancer cachexia. Blocking the synthesis or action of acute phase reactants and cytokines is a feasible therapeutic strategy, but no anti-cytokine therapies are currently approved for use in PC. Metabolic alterations such as increased energy expenditure and gluconeogenesis, insulin resistance, fat tissue browning, excessive oxidative stress, and proteolysis with amino acid mobilization support tumor growth and the development of cachexia. Current innovative nutritional strategies for cachexia management include ketogenic diet, utilization of natural compounds such as silibinin, and supplementation with ω3-polyunsaturated fatty acids. Elevated ketone bodies exhibit an anticancer and anticachectic effect. Silibinin has been shown to inhibit growth of PC cells, induce metabolic alterations, and reduce myofiber degradation. Consumption of ω3-polyunsaturated fatty acids has been shown to significantly decrease resting energy expenditure and regulate metabolic dysfunction.
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Affiliation(s)
- Anastasiya Yakovenko
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Miles Cameron
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - Jose Gilberto Trevino
- Department of Surgery, University of Florida Health Sciences Center, Gainesville, Florida 32610, United States
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48
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Differential Metabolic Responses to Adipose Atrophy Associated with Cancer Cachexia and Caloric Restriction in Rats and the Effect of Rikkunshito in Cancer Cachexia. Int J Mol Sci 2018; 19:ijms19123852. [PMID: 30513935 PMCID: PMC6321026 DOI: 10.3390/ijms19123852] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 11/17/2018] [Accepted: 11/24/2018] [Indexed: 12/24/2022] Open
Abstract
Despite the similar phenotypes, including weight loss, reduction of food intake, and lower adiposity, associated with caloric restriction (CR) and cancer cachexia (CC), CC is a progressive wasting syndrome, while mild CR improves whole body metabolism. In the present study, we compared adipose metabolic changes in a novel rat model of CC, mild CR (70% of the food intake of control rats, which is similar to the food consumption of CC rats), and severe CR (30% of the food intake of controls). We show that CC and severe CR are associated with much smaller adipocytes with significantly lower mitochondrial DNA content; but, that mild CR is not. CC and both mild and severe CR similarly upregulated proteins involved in lipolysis. CC also downregulated proteins involved in fatty acid biosynthesis, but mild CR upregulated these. These findings suggest that CC might impair de novo fatty acid biosynthesis and reduce mitochondrial biogenesis, similar to severe CR. We also found that rikkunshito, a traditional Japanese herbal medicine, does not ameliorate the enhanced lipolysis and mitochondrial impairment, but rather, rescues de novo fatty acid biosynthesis, suggesting that rikkunshito administration might have partially similar effects to mild CR.
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49
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Hou YC, Wang CJ, Chao YJ, Chen HY, Wang HC, Tung HL, Lin JT, Shan YS. Elevated Serum Interleukin-8 Level Correlates with Cancer-Related Cachexia and Sarcopenia: An Indicator for Pancreatic Cancer Outcomes. J Clin Med 2018; 7:jcm7120502. [PMID: 30513776 PMCID: PMC6306800 DOI: 10.3390/jcm7120502] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 11/20/2018] [Accepted: 11/28/2018] [Indexed: 01/06/2023] Open
Abstract
Cancer cachexia (CC), characterized by body weight loss and sarcopenia, contributes to over 20% of all cancer-related death. Approximately 80% of pancreatic cancer (PC) patients develop CC during disease progression. Pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, have been correlated with CC; however, its prognostic significance remains unclear. In this study, serum levels of the CC-related cytokines were determined in normal donors and PC patients. IL-8 expression was assessed in PC tissue microarrays. The correlation of levels of each cytokine with disease progression, weight loss, and sarcopenia was calculated. The relationships among the baseline variables, CC, and IL-8 expression with disease progression were examined using univariate and multivariate analyses. Of these mentioned cytokines, only serum IL-8 level was elevated in the locally advanced group (n = 55) compared with the normal (n = 17) and resected groups (n = 55). Serum IL-8 level was positively correlated with CC status, weight loss, sarcopenia, but was negatively correlated with total psoas area (TPA). IL-8 expression in tissue samples was also positively associated with weight loss. Furthermore, serum IL-8 level was an independent predictor of survival. In conclusion, elevated serum IL-8 level significantly correlates with CC and sarcopenia and can be used as a prognostic indicator in PC.
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Affiliation(s)
- Ya-Chin Hou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
- Department of Clinical Medical Research, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
| | - Chih-Jung Wang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
| | - Ying-Jui Chao
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
| | - Hao-Yun Chen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
| | - Hao-Chen Wang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
- Department of Clinical Medical Research, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
| | - Hui-Ling Tung
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
| | - Jung-Ting Lin
- School of Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
- Department of Clinical Medical Research, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.
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50
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Liu J, Song N, Huang Y, Chen Y. Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway. Sci Rep 2018; 8:15247. [PMID: 30323244 PMCID: PMC6189061 DOI: 10.1038/s41598-018-33229-w] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 09/25/2018] [Indexed: 01/10/2023] Open
Abstract
Irisin, a recently identified myokine that is released from skeletal muscle following exercise, regulates body weight and influences various metabolic diseases such as obesity and diabetes. In this study, human recombinant nonglycosylated P-irisin (expressed in Escherichia coli prokaryote cell system) or glycosylated E-irisin (expressed in Pichia pastoris eukaryote cell system) were compared to examine the role of recombinant irisin against pancreatic cancer (PC) cells lines, MIA PaCa-2 and Panc03.27. MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-di phenyltetrazolium bromide] and cell colony formation assays revealed that irisin significantly inhibited the growth of MIA PaCa-2 and Panc03.27 in a dose-dependent manner. Irisin also induced G1 arrest in both cell lines. Scratch wound healing and transwell assays revealed that irisin also inhibited the migration of PC cells. Irisin reversed the activity of epithelial–mesenchymal transition (EMT) while increasing E-cadherin expression and reducing vimentin expression. Irisin activated the adenosine monophosphate-activated protein kinase (AMPK) pathway and suppressed the mammalian target of rapamycin (mTOR) signaling. Besides, our results suggest that irisin receptors exist on the surface of human MIA PaCa-2 and Panc03.27 cells. Our results clearly demonstrate that irisin suppressed PC cell growth via the activation of AMPK, thereby downregulating the mTOR pathway and inhibiting EMT of PC cells.
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Affiliation(s)
- Jiayu Liu
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, 2699 Qianjin Street, Changchun, 130012, China.,School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Nannan Song
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, 2699 Qianjin Street, Changchun, 130012, China.,School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Yibing Huang
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, 2699 Qianjin Street, Changchun, 130012, China.,School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Yuxin Chen
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, 2699 Qianjin Street, Changchun, 130012, China. .,School of Life Sciences, Jilin University, Changchun, 130012, China.
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