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Kim YE, Yu MH, Nam CM, Kang ES. Effects of Pancreatitis and Type 2 Diabetes Mellitus on the Development of Pancreatic Cancer: A Nationwide Nested Case-Control Study (Diabetes Metab J 2025;49:252-63). Diabetes Metab J 2025; 49:522-523. [PMID: 40367993 PMCID: PMC12086581 DOI: 10.4093/dmj.2025.0314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2025] Open
Affiliation(s)
- Young-eun Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Min Heui Yu
- SENTINEL Team, Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Chung Mo Nam
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Health Services Research, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Juza A, Kołodziej-Spirodek L, Gutkowski K, Partyka M, Dąbrowski M. Distinguishing exocrine pancreas disease-associated diabetes from type 2 diabetes based on anthropometric and metabolic parameters. World J Diabetes 2025; 16:95102. [PMID: 39959260 PMCID: PMC11718472 DOI: 10.4239/wjd.v16.i2.95102] [Citation(s) in RCA: 1] [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: 04/01/2024] [Revised: 08/28/2024] [Accepted: 10/29/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Adult-onset diabetes is most often considered to be type 2 diabetes. However, other types of diabetes can develop in adults, including exocrine pancreas disease-associated diabetes, also called type 3c diabetes. Differential diagnosis between these types of diabetes still remains a diagnostic challenge. AIM To define anthropometric and laboratory markers that will allow for early diagnosis of pancreatic disease-associated diabetes. METHODS The study group included 44 patients with pancreatogenic diabetes (26 with pancreatic cancer and 18 with chronic pancreatitis), while the control group consisted of 35 patients with type 2 diabetes. We analyzed several parameters, including sex, age, body mass index (BMI), fasting plasma glucose, fasting C-peptide and insulin with homeostasis model assessment of insulin resistance (HOMA-IR) index calculation, adrenomedullin, adiponectin and creatinine levels with epidermal growth factor receptor (eGFR) calculation. We also developed an equation, termed type 3c diabetes index, which utilized BMI, fasting insulin and adrenomedullin levels, and eGFR to better identify patients with type 3c diabetes. RESULTS Compared to patients with type 2 diabetes, patients with pancreatogenic diabetes had significantly lower BMI (25.11 ± 4.87 kg/m2 vs 30.83 ± 5.21 kg/m2), fasting C-peptide (0.81 ± 0.42 nmol/L vs 1.71 ± 0.80 nmol/L), insulin (76.81 ± 63.34 pmol/L vs 233.19 ± 164.51 pmol/L) and HOMA-IR index, despite similar fasting plasma glucose levels. Patients with pancreatogenic diabetes also had lower adrenomedullin levels (0.41 ± 0.25 ng/mL vs 0.63 ± 0.38 ng/mL) but higher adiponectin levels (13.08 ± 7.20 μg/mL vs 8.28 ± 4.01 μg/mL) and eGFR levels (100.53 ± 21.60 mL/min/1.73 m2 vs 85.14 ± 19.24 mL/min/1.73 m2). Finally, patients with pancreatogenic diabetes had significantly lower Type 3c diabetes index values. CONCLUSION Patients with pancreatogenic diabetes differ from patients with type 2 diabetes in anthropometric and laboratory parameters. The type 3c diabetes index had the highest discriminating value, above any single parameter.
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Affiliation(s)
- Anna Juza
- College of Medical Sciences, Institute of Medical Sciences, University of Rzeszów, Rzeszów 35-959, Poland
- Diabetic Outpatient Clinic & Department of Gastroenterology and Hepatology with the Subunit of Internal Diseases, University Clinical Hospital, Rzeszów 35-055, Poland
| | - Lilianna Kołodziej-Spirodek
- Diabetic Outpatient Clinic & Department of Gastroenterology and Hepatology with the Subunit of Internal Diseases, University Clinical Hospital, Rzeszów 35-055, Poland
| | - Krzysztof Gutkowski
- College of Medical Sciences, Institute of Medical Sciences, University of Rzeszów, Rzeszów 35-959, Poland
| | - Mariusz Partyka
- College of Medical Sciences, Institute of Medical Sciences, University of Rzeszów, Rzeszów 35-959, Poland
- Department of Internal Diseases, Nephrology and Endocrinology with the Nuclear Medicine Laboratory and the Dialysis Center & Endocrinology Outpatient Clinic, Clinical Provincial Hospital No. 2 in Rzeszów, Rzeszów 35-301, Poland
| | - Mariusz Dąbrowski
- College of Medical Sciences, Institute of Medical Sciences, University of Rzeszów, Rzeszów 35-959, Poland
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Szablewski L. Associations Between Diabetes Mellitus and Neurodegenerative Diseases. Int J Mol Sci 2025; 26:542. [PMID: 39859258 PMCID: PMC11765393 DOI: 10.3390/ijms26020542] [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: 10/31/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years and older are type 2 diabetes mellitus (T2DM) and cognitive impairment. It was found that diabetes mellitus is a major risk for cognitive decline, dementia, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Different mechanisms of associations between these diseases and diabetes mellitus have been suggested. For example, it is postulated that an impaired intracellular insulin signaling pathway, together with hyperglycemia and hyperinsulinemia, may cause pathological changes, such as dysfunction of the mitochondria, oxidative stress inflammatory responses, etc. The association between diabetes mellitus and neurodegenerative diseases, as well as the mechanisms of these associations, needs further investigation. The aim of this review is to describe the associations between diabetes mellitus, especially type 1 (T1DM) and type 2 diabetes mellitus, and selected neurodegenerative diseases, i.e., Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Suggested mechanisms of these associations are also described.
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Affiliation(s)
- Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, Poland
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Harne PS, Harne V, Wray C, Thosani N. Endoscopic innovations in diagnosis and management of pancreatic cancer: a narrative review and future directions. Therap Adv Gastroenterol 2024; 17:17562848241297434. [PMID: 39664230 PMCID: PMC11632891 DOI: 10.1177/17562848241297434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 10/15/2024] [Indexed: 12/13/2024] Open
Abstract
Pancreatic cancer serves as the third leading cause of cancer-associated morbidity and mortality in the United States, with a 5-year survival rate of only 12% with an expected increase in incidence and mortality in the coming years. Pancreatic ductal adenocarcinomas constitute most pancreatic malignancies. Certain genetic syndromes, including Lynch syndrome, hereditary breast and ovarian cancer syndrome, hereditary pancreatitis, familial adenomatous polyposis, Peutz-Jeghers syndrome, familial pancreatic cancer mutation, and ataxia telangiectasia, confer a significantly higher risk. Screening for pancreatic malignancies currently targets patients with germline mutations or those with significant family history. Screening the general population is not currently viable owing to overall low incidence and lack of specific tests. Endoscopic ultrasound (EUS) and its applied advances are increasingly being used for surveillance, diagnosis, and management of pancreatic malignancies and have now become an indispensable tool in their management. For patients with risk factors, EUS in combination with magnetic resonance imaging/magnetic resonance cholangiopancreatography is used for screening. The role of endoscopic modalities has been expanding with the increased utilization of endoscopic retrograde cholangiopancreatography, EUS-directed therapies include EUS-guided fine-needle aspiration and EUS-fine-needle biopsy (FNB). EUS combined with FNB has the highest specificity and sensitivity for detecting pancreatic cancer amongst available modalities. Studies also recognize that artificial intelligence assisted EUS in the early detection of pancreatic cancer. At the same time, surgical resection has been historically considered the only curative treatment for pancreatic cancer, over 80% of patients present with unresectable disease. We also discuss EUS-guided therapies of physicochemicals (radiofrequency ablation, brachytherapy, and intratumor chemotherapy), biological agents (gene therapies and oncolytic viruses), and immunotherapy. We aim to perform a detailed review of the current burden, risk factors, role of screening, diagnosis, and endoscopic advances in the treatment modalities available for pancreatic cancer.
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Affiliation(s)
- Prateek Suresh Harne
- Division of Gastroenterology, Allegheny Health Network, Pittsburgh, PA 15212, USA
| | - Vaishali Harne
- Division of Pediatric Gastroenterology, The University of Texas
- Health Science Center and McGovern School of Medicine, Houston, TX, USA
| | - Curtis Wray
- Department of Surgery, The University of Texas Health Science Center and McGovern School of Medicine, Houston, TX, USA
| | - Nirav Thosani
- Department of Surgery and Interventional Gastroenterology, The University of Texas
- Health Science Center and McGovern School of Medicine, Houston, TX, USA
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Wlodarczyk B, Durko L, Walczak K, Talar-Wojnarowska R, Malecka-Wojciesko E. Select Endocrine Disorders and Exosomes in Early PDAC Diagnosis. Int J Mol Sci 2024; 25:12159. [PMID: 39596226 PMCID: PMC11594802 DOI: 10.3390/ijms252212159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/01/2024] [Accepted: 11/03/2024] [Indexed: 11/28/2024] Open
Abstract
Disturbances in carbohydrate metabolism are suggested to be the early symptoms of pancreatic ductal adenocarcinoma (PDAC). The accumulated data suggests that endocrine function-related biomarkers may represent a breakthrough in the early detection of PDAC. Factors which may predispose one to the development of PDAC are insulin resistance and hyperinsulinemia. Elevated insulin levels induce the onset of carcinogenesis by altering the differentiation and function of islet cells through stimulating growth factors, including insulin-like growth factors (IGFs). Impaired β cell function, along with the impact of PDAC-released factors (e.g., adrenomedullin (ADM), IGF-1, and macrophage inhibitory factor (MIF) on pancreatic islets, may contribute to the induction of diabetes associated with PDAC. Recently, exosomes have attracted worldwide attention due to their role in varied features of cell function, particularly in cancer progression. Exosomes comprise of small extracellular vesicles produced by almost all cells. These vesicles contain a vast array of biomolecules, including proteins and microRNAs. Exosomes participate in cancer growth and promote angiogenesis. They promote tumorigenesis and metastasis, and are associated with the acquisition of cancer cells resistant to chemotherapy. Data have been accumulating recently on the role of exosomes in the rapid recognition, prognosis and potential therapy of pancreatic cancer.
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Affiliation(s)
- Barbara Wlodarczyk
- Department of Digestive Tract Diseases, Medical University of Lodz, 90-153 Lodz, Poland
| | - Lukasz Durko
- Department of Digestive Tract Diseases, Medical University of Lodz, 90-153 Lodz, Poland
| | - Konrad Walczak
- Department of Internal Diseases and Nephrodiabetology, Medical University of Lodz, 90-549 Lodz, Poland
| | | | - Ewa Malecka-Wojciesko
- Department of Digestive Tract Diseases, Medical University of Lodz, 90-153 Lodz, Poland
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Ye XW, Wang ZY, Shao YX, Tang YC, Dong XJ, Zhu YN. Monocyte to high-density lipoprotein ratio based prognostic nomogram for patients following allogeneic vascular replacement pancreaticoduodenectomy. Front Genet 2024; 15:1465318. [PMID: 39253716 PMCID: PMC11381275 DOI: 10.3389/fgene.2024.1465318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/12/2024] [Indexed: 09/11/2024] Open
Abstract
Background Preoperative immune-inflammatory condition influencing the metabolism of malignancies. We sought to investigate the prognostic value of a novel immune-inflammatory metabolic marker, the monocyte-to-high-density lipoprotein ratio (MHR), in patients with locally advanced pancreatic cancer. Methods A retrospective analysis was conducted on the clinical data of 118 patients with locally advanced pancreatic cancer and obstructive jaundice who underwent allogeneic vascular replacement pancreaticoduodenectomy in our hospital from Apr. 2011 to Dec. 2023. To assess the predictive capacity of immune-inflammatory metabolic marker, we utilized the area under the receiver operating characteristic curve (AUC-ROC) and assessed the predictive potential of MHR in forecasting outcomes through both univariate and multivariate Cox proportional hazard analyses. Results The area under AUC for MHR in predicting 1-year postoperative survival was 0.714, with an optimal cutoff value of 1.184, yielding a sensitivity of 78.9% and specificity of 66.2%. Based on this cutoff value, patients were divided into a low MHR group (MHR ≤1.184, n = 61) and a high MHR group (MHR >1.184, n = 57). The median survival times for the low and high MHR groups were 27.0 months and 12.0 months, respectively (χ2 = 30.575, p < 0.001), and the median DFS were 18.0 months and 8.0 months, respectively (χ2 = 26.330, p < 0.001). Univariate and multivariate analyses indicated that preoperative MHR, preoperative creatinine, operation duration, and TNM stage were independent predictors of postoperative mortality, while preoperative MHR, preoperative creatinine, and TNM stage were independent predictors of postoperative recurrence risk. Conclusion MHR, as an independent immune-inflammatory metabolic predictor of OS and DFS in patients with advanced PC after pancreaticoduodenectomy. Early monitoring and reduction of MHR may be of great significance in improving prognosis.
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Affiliation(s)
- Xiao-Wen Ye
- Department of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, China
| | - Zu-Yu Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yun-Xia Shao
- Department of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, China
| | - Ying-Chun Tang
- Department of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, China
| | - Xiong-Jun Dong
- Department of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, China
| | - Ya-Ning Zhu
- Department of Nephrology, Wuhu Hospital, East China Normal University, Wuhu, China
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Grigorescu RR, Husar-Sburlan IA, Gheorghe C. Pancreatic Cancer: A Review of Risk Factors. Life (Basel) 2024; 14:980. [PMID: 39202722 PMCID: PMC11355429 DOI: 10.3390/life14080980] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/28/2024] [Accepted: 08/01/2024] [Indexed: 09/03/2024] Open
Abstract
Pancreatic adenocarcinoma is one of the most lethal types of gastrointestinal cancer despite the latest medical advances. Its incidence has continuously increased in recent years in developed countries. The location of the pancreas can result in the initial symptoms of neoplasia being overlooked, which can lead to a delayed diagnosis and a subsequent reduction in the spectrum of available therapeutic options. The role of modifiable risk factors in pancreatic cancer has been extensively studied in recent years, with smoking and alcohol consumption identified as key contributors. However, the few screening programs that have been developed focus exclusively on genetic factors, without considering the potential impact of modifiable factors on disease occurrence. Thus, fully understanding and detecting the risk factors for pancreatic cancer represents an important step in the prevention and early diagnosis of this type of neoplasia. This review reports the available evidence on different risk factors and identifies the areas that could benefit the most from additional studies.
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Affiliation(s)
- Raluca Roxana Grigorescu
- Gastroenterology Department, “Sfanta Maria” Hospital, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | | | - Cristian Gheorghe
- Center for Digestive Disease and Liver Transplantation, Fundeni Clinical Institute, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Song Y, Jiang L, Han Y, Zhang S, Li S. Triglyceride-glucose index and glycemic dynamics in pancreatic ductal adenocarcinoma: implications for disease progression and prognosis. J Transl Med 2024; 22:708. [PMID: 39080703 PMCID: PMC11290143 DOI: 10.1186/s12967-024-05524-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/20/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND To elucidate the relationship between the triglyceride-glycemic index (TyG) and clinical characteristics of pancreatic ductal adenocarcinoma (PDAC). METHODS A total of 1,594 individuals diagnosed with pancreatic and periampullary neoplasms were categorized into four groups: PDAC-early (n = 403), locally advanced PDAC (LAPC, n = 315), PDAC-late with distant metastasis (n = 371), and other tumor types (n = 505). TyG-high was defined as a TyG index greater than 8.81 in males and 8.73 in females. RESULTS The prevalence of TyG-high status was highest in PDAC-early (68.48%), followed by LAPC (53.33%), and lowest in PDAC-late (44.47%). TyG-high status significantly predicted worse PDAC prognosis (P = 0.0166), particularly in PDAC-late (P = 0.0420). Despite similar blood glucose levels across PDAC groups (P = 0.897), PDAC-early patients showed significantly higher rates of glycemic disturbances (56.33% vs. 32.28%) and TyG-high status (68.48% vs. 47.13%) compared to those with other tumors. Progressive increases in glycemic disturbances and TyG-high status were observed from benign to pre-malignant lesions and PDAC-early. PDAC-early patients at the pancreatic head exhibited higher rates of glycemic disturbances (58.12% vs. 33.33%, P < 0.0001), larger pancreatic duct diameters (0.4056 cm vs. 0.3398 cm, P = 0.0043), and poorer prognosis compared to periampullary cancers, although the TyG-high rate and body mass index were similar. CONCLUSION The TyG index exhibits a complex association with PDAC stages, profoundly shaping glycemic profiles. At the initial stages of PDAC, a notable elevation in TyG-high status and glycemic disturbances is observed. However, in advanced PDAC, while the TyG-high rate diminishes, abnormal glucose levels persist.
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Affiliation(s)
- Yunda Song
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Lingmin Jiang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Yuanxia Han
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Subo Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China.
| | - Shengping Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China.
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
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Topkan E, Senyurek S, Kılic Durankus N, Ozturk D, Selek U. Novel Somay's GLUCAR Index Efficiently Predicts Survival Outcomes in Locally Advanced Pancreas Cancer Patients Receiving Definitive Chemoradiotherapy: A Propensity-Score-Matched Cohort Analysis. J Pers Med 2024; 14:746. [PMID: 39064000 PMCID: PMC11278407 DOI: 10.3390/jpm14070746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Propensity score matching (PSM) was used to investigate the prognostic value of a novel GLUCAR index [Glucose × (C-reactive protein ÷ albumin)] in unresectable locally advanced pancreatic cancer (LA-NPC) patients who received definitive concurrent chemoradiotherapy (CCRT). METHODS The PSM analysis comprised 142 LA-PAC patients subjected to definitive CCRT. Receiver operating characteristic (ROC) curve analysis was utilized to identify relevant pre-CCRT cutoffs that could effectively stratify survival results. The primary and secondary objectives were the correlations between the pre-CCRT GLUCAR measures and overall survival (OS) and progression-free survival (PFS). RESULTS The ROC analysis revealed significance at 43.3 for PFS [area under the curve (AUC): 85.1%; sensitivity: 76.8%; specificity: 74.2%; J-index: 0.510)] and 42.8 for OS (AUC: 81.8%; sensitivity: 74.2%; specificity: 71.7%; J-index: 0.459). Given that these cutoff points were close, the standard cutoff point, 42.8, was selected for further analysis. Comparative survival analyses showed that pre-CCRT GLUCAR ≥ 42.8 (n = 71) measures were associated with significantly shorter median PFS (4.7 vs. 15.8 months; p < 0.001) and OS (10.1 vs. 25.4 months; p < 0.001) durations compared to GLUCAR < 42.8 measures (n = 71). The multivariate analysis results confirmed the independent significance of the GLUCAR index on PFS (p < 0.001) and OS (p < 0.001) outcomes. CONCLUSIONS Elevated pre-CCRT GLUCAR levels are robustly and independently linked to significantly poorer PFS and OS outcomes in unresectable LA-PAC patients treated with definitive CCRT.
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Affiliation(s)
- Erkan Topkan
- Department of Radiation Oncology, Faculty of Medicine, Baskent University, Adana 01120, Turkey
| | - Sukran Senyurek
- Department of Radiation Oncology, Koc University School of Medicine, Istanbul 34450, Turkey; (S.S.); (N.K.D.); (U.S.)
| | - Nulifer Kılic Durankus
- Department of Radiation Oncology, Koc University School of Medicine, Istanbul 34450, Turkey; (S.S.); (N.K.D.); (U.S.)
| | - Duriye Ozturk
- Department of Radiation Oncology, Faculty of Medicine, Afyonkarahisar Health Sciences University, Afyonkarahisar 03030, Turkey;
| | - Ugur Selek
- Department of Radiation Oncology, Koc University School of Medicine, Istanbul 34450, Turkey; (S.S.); (N.K.D.); (U.S.)
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Pliszka M, Szablewski L. Associations between Diabetes Mellitus and Selected Cancers. Int J Mol Sci 2024; 25:7476. [PMID: 39000583 PMCID: PMC11242587 DOI: 10.3390/ijms25137476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8-18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association.
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Affiliation(s)
- Monika Pliszka
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
| | - Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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11
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An H, Dai H, Liu X. Changing Trends in the Global Disease Burden of Pancreatic Cancer from 1990 to 2030. Dig Dis Sci 2024; 69:2450-2461. [PMID: 38722410 DOI: 10.1007/s10620-024-08465-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 04/23/2024] [Indexed: 07/19/2024]
Abstract
AIM To explore the global burden of pancreatic cancer (PC) from 1990 to 2019, evaluate independent effects of age, period, and cohort on the incidence of PC, and predict the incidence of PC in the next decade. METHODS Data were obtained from the Global Burden of Disease Study 2019. We calculated the age-standardized disability-adjusted life years (DALY) rate, age-standardized mortality rate (ASMR), age-standardized incidence rate (ASIR), and age-standardized prevalence rate (ASPR) of PC. Joinpoint Poisson regression analysis was performed to identify the temporal trends in the incidence of PC. Then, a two-factor model was constructed using the Poisson log-linear model, and a three-factor model was constructed using the intrinsic estimator (IE) method to estimate the independent effects of age, period, and cohort on the incidence of PC. Finally, the Bayesian age-period-cohort (BAPC) model was also used to predict the age-standardized global incidence rate of PC and age-standardized new PC cases from 2020 to 2030. RESULTS Overall, the DALY rate, ASMR, ASIR, and ASPR all increased from 1990 to 2019. The ASIR in males increased from 6 per 100,000 in 1990 to 7.5 per 100,000 in 2019 and was predicted to rise to 8.2 per 100,000 by 2030. Meanwhile, the ASIR in females rose from 4.5 per 100,000 in 1990 to 5.7 per 100,000 in 2019 and was predicted to rise to 6.3 per 100,000 by 2030. The age effect on the incidence of PC showed sharp increasing trends from 40 to 79 years. The period effect continuously increased with advancing periods, but the cohort effect showed substantial decreasing trends. CONCLUSIONS The age and period effect on the incidence of PC presented increasing trends, while the cohort effect showed decreasing trends. All indicators of the global burden of PC are increasing in both males and females, and the ASIR is predicted to rise at an alarming rate by 2030. Thus, timely screening and intervention are recommended, especially for earlier birth cohorts at high risk.
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Affiliation(s)
- Haoyu An
- School of Medicine, The Chinese University of Hong Kong, Shatin, 999077, NT, Hong Kong.
| | - Hanqian Dai
- Tianyuan Honors School, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Xiaomeng Liu
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
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Wayne CD, Benbetka C, Besner GE, Narayanan S. Challenges of Managing Type 3c Diabetes in the Context of Pancreatic Resection, Cancer and Trauma. J Clin Med 2024; 13:2993. [PMID: 38792534 PMCID: PMC11122338 DOI: 10.3390/jcm13102993] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/04/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Type 3c diabetes mellitus (T3cDM), also known as pancreatogenic or pancreoprivic diabetes, is a specific type of DM that often develops as a result of diseases affecting the exocrine pancreas, exhibiting an array of hormonal and metabolic characteristics. Several pancreatic exocrine diseases and surgical procedures may cause T3cDM. Diagnosing T3cDM remains difficult as the disease characteristics frequently overlap with clinical presentations of type 1 DM (T1DM) or type 2 DM (T2DM). Managing T3cDM is likewise challenging due to numerous confounding metabolic dysfunctions, including pancreatic endocrine and exocrine insufficiencies and poor nutritional status. Treatment of pancreatic exocrine insufficiency is of paramount importance when managing patients with T3cDM. This review aims to consolidate the latest information on surgical etiologies of T3cDM, focusing on partial pancreatic resections, total pancreatectomy, pancreatic cancer and trauma.
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Affiliation(s)
- Colton D. Wayne
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Surgery, Baylor University Medical Center, 3600 Gaston Ave, Dallas, TX 75246, USA
| | | | - Gail E. Besner
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Siddharth Narayanan
- Department of Pediatric Surgery, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205, USA; (C.D.W.); (G.E.B.)
- Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH 43205, USA
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13
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Wang H, Ruan S, Wu Z, Yan Q, Chen Y, Cui J, Zhang Z, Huang S, Hou B, Zhang C. Prognostic significance of glucose-lipid metabolic index in pancreatic cancer patients with diabetes mellitus. Cancer Med 2024; 13:e7108. [PMID: 38523554 PMCID: PMC10961598 DOI: 10.1002/cam4.7108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 12/22/2023] [Accepted: 03/04/2024] [Indexed: 03/26/2024] Open
Abstract
BACKGROUND The incidence of pancreatic cancer (PC) is higher in diabetic patients due to disturbances in glucose and lipid metabolism caused by insulin resistance (IR). However, the effect of diabetes as well as IR on the prognosis of PC patients remains inconclusive. Our study aims to assess the impact of IR on the prognosis of PC patients with diabetes. METHODS We conducted a retrospective analysis of 172 PC patients with diabetes in our institute from 2015 to 2021. Prognostic assessment was performed using univariate/multifactorial analysis and survival analysis. The predictive efficacy of metabolic indices was compared using receiver operator characteristic (ROC) curve analysis. RESULTS One hundred twenty-one of 172 patients died during follow-up, with a median follow-up of 477 days and a median overall survival (OS) of 270 days. Survival analysis showed a significant difference in OS by IR related parameters, which were triglyceride-glucose index (TyG), triglyceride-glucose index-body mass index (TyG-BMI), and triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-c). The ROC curve indicated that TyG, TyG-BMI, and TG/HDL-c had prognostic efficacy for PC with diabetes. We next optimized TyG-BMI and obtained a new parameter, namely glucose-lipid metabolism index (GLMI), and the patients were classified into GLMI low group and high group based on the calculated cutoff value. The GLMI high group had higher TyG, TyG-BMI, TyG/HDL-c, BMI, TG, total cholesterol (TC), TC/HDL-c, fasting plasma glucose, CA199, and more advanced tumor stage compared to low group. Univariate and multivariate analyses showed that GLMI was an independent prognostic factor. Furthermore, the patients of GLMI high group had worse OS compared to low group and the ROC curves showed GLMI had better predictive ability than TyG and TyG-BMI. CONCLUSIONS IR is associated with the outcome of PC patients with diabetes and higher level of IR indicates worse prognosis. GLMI has a good predictive value for PC with diabetes.
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Affiliation(s)
- Hailiang Wang
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- Department of Hepatobiliary SurgeryWeihai Central Hospital, Qingdao UniversityWeihaiChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
| | - Shiye Ruan
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
| | - Zelong Wu
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
| | - Qian Yan
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- School of Medicine South China University of TechnologyGuangzhouChina
| | - Yubin Chen
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- School of Medicine South China University of TechnologyGuangzhouChina
| | - Jinwei Cui
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- School of Medicine South China University of TechnologyGuangzhouChina
| | - Zhongyan Zhang
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
| | - Shanzhou Huang
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
- School of Medicine South China University of TechnologyGuangzhouChina
| | - Baohua Hou
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
- School of Medicine South China University of TechnologyGuangzhouChina
- Department of General SurgeryHeyuan People's HospitalHeyuanChina
| | - Chuanzhao Zhang
- Department of General Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhouChina
- School of Medicine South China University of TechnologyGuangzhouChina
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14
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Pourali G, Donyadideh G, Mehrabadi S, Hamid F, Hassanian SM, Ferns GA, Khazaei M, Avan A. Clinical practice guidelines for interventional treatment of pancreatic cancer. RECENT ADVANCES IN NANOCARRIERS FOR PANCREATIC CANCER THERAPY 2024:345-373. [DOI: 10.1016/b978-0-443-19142-8.00008-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2025]
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15
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Schranz A, Sternad C, Aziz F, Wagner D, Kornprat P, Sucher R, Jost PJ, Wölfler A, Pieber TR, Sourij H, Riedl JM, Aberer F. Incidence of Diabetes Mellitus and Its Impact on Outcomes in Patients Undergoing Surgical Pancreatectomy for Non-Malignant and Malignant Pancreatobiliary Diseases-A Retrospective Analysis. J Clin Med 2023; 12:7532. [PMID: 38137600 PMCID: PMC10744322 DOI: 10.3390/jcm12247532] [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: 10/27/2023] [Revised: 11/30/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
Diabetes mellitus (DM) is a prominent risk factor for malignant and non-malignant pancreatic diseases. Furthermore, the presence of DM predicts an unfavourable outcome in people with pancreatic cancer. This retrospective observational study investigated 370 patients who underwent pancreatic resection surgery for various indications (84.3% in malignant indication) in a single surgery centre in Graz, Austria. The preoperative and postoperative diabetes statuses were evaluated according to surgery method and disease entity and predictors for diabetes development after surgery, as well as outcomes (survival and cancer recurrence) according to diabetes status, were analysed. In the entire cohort, the postoperative diabetes (postopDM) incidence was 29%. PostopDM occurred significantly more frequently in malignoma patients than in those with benign diseases (31.3% vs. 16.7%; p = 0.040, OR = 2.28). In the malignoma population, BMI, longer surgery duration, and prolonged ICU and hospital stay were significant predictors of diabetes development. The 1- and 2-year follow-ups showed a significantly increased mortality of people with postopDM in comparison to people without diabetes (HR 1-year = 2.02, p = 0.014 and HR 2-years = 1.56, p = 0.034). Local cancer recurrence was not influenced by the diabetes status. Postoperative new-onset diabetes seems to be associated with higher mortality of patients with pancreatic malignoma undergoing pancreatobiliary surgery.
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Affiliation(s)
- Anna Schranz
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria; (A.S.); (C.S.); (F.A.); (T.R.P.); (F.A.)
| | - Christoph Sternad
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria; (A.S.); (C.S.); (F.A.); (T.R.P.); (F.A.)
| | - Faisal Aziz
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria; (A.S.); (C.S.); (F.A.); (T.R.P.); (F.A.)
| | - Doris Wagner
- Department of Surgery, Medical University of Graz, 8036 Graz, Austria; (D.W.); (P.K.); (R.S.)
| | - Peter Kornprat
- Department of Surgery, Medical University of Graz, 8036 Graz, Austria; (D.W.); (P.K.); (R.S.)
| | - Robert Sucher
- Department of Surgery, Medical University of Graz, 8036 Graz, Austria; (D.W.); (P.K.); (R.S.)
| | - Philipp J. Jost
- Department of Internal Medicine, Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (P.J.J.); (J.M.R.)
| | - Albert Wölfler
- Department of Internal Medicine, Division of Hematology, Medical University of Graz, 8036 Graz, Austria;
| | - Thomas R. Pieber
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria; (A.S.); (C.S.); (F.A.); (T.R.P.); (F.A.)
| | - Harald Sourij
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria; (A.S.); (C.S.); (F.A.); (T.R.P.); (F.A.)
| | - Jakob M. Riedl
- Department of Internal Medicine, Division of Oncology, Medical University of Graz, 8036 Graz, Austria; (P.J.J.); (J.M.R.)
| | - Felix Aberer
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8036 Graz, Austria; (A.S.); (C.S.); (F.A.); (T.R.P.); (F.A.)
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16
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Chen S, Phuc PT, Nguyen P, Burton W, Lin S, Lin W, Lu CY, Hsu M, Cheng C, Hsu JC. A novel prediction model of the risk of pancreatic cancer among diabetes patients using multiple clinical data and machine learning. Cancer Med 2023; 12:19987-19999. [PMID: 37737056 PMCID: PMC10587954 DOI: 10.1002/cam4.6547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/14/2023] [Accepted: 09/06/2023] [Indexed: 09/23/2023] Open
Abstract
INTRODUCTION Pancreatic cancer is associated with poor prognosis. Considering the increased global incidence of diabetes cases and that individuals with diabetes are considered a high-risk subpopulation for pancreatic cancer, it is critical to detect the risk of pancreatic cancer within populations of person living = with diabetes. This study aimed to develop a novel prediction model for pancreatic cancer risk among patients with diabetes, using = a real-world database containing clinical features and employing numerous artificial intelligent approach algorithms. METHODS This retrospective observational study analyzed data on patients with Type 2 diabetes from a multisite Taiwanese EMR database between 2009 and 2019. Predictors were selected in accordance with the literature review and clinical perspectives. The prediction models were constructed using machine learning algorithms such as logistic regression, linear discriminant analysis, gradient boosting machine, and random forest. RESULTS The cohort consisted of 66,384 patients. The Linear Discriminant Analysis (LDA) model generated the highest AUROC of 0.9073, followed by the Voting Ensemble and Gradient Boosting machine models. LDA, the best model, exhibited an accuracy of 84.03%, a sensitivity of 0.8611, and a specificity of 0.8403. The most significant predictors identified for pancreatic cancer risk were glucose, glycated hemoglobin, hyperlipidemia comorbidity, antidiabetic drug use, and lipid-modifying drug use. CONCLUSION This study successfully developed a highly accurate 4-year risk model for pancreatic cancer in patients with diabetes using real-world clinical data and multiple machine-learning algorithms. Potentially, our predictors offer an opportunity to identify pancreatic cancer early and thus increase prevention and invention windows to impact survival in diabetic patients.
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Affiliation(s)
- Shih‐Min Chen
- School of PharmacyTaipei Medical UniversityTaipeiTaiwan
| | - Phan Thanh Phuc
- International Ph.D. Program in Biotech and Healthcare Management, College of ManagementTaipei Medical UniversityTaipeiTaiwan
| | - Phung‐Anh Nguyen
- Clinical Data Center, Office of Data ScienceTaipei Medical UniversityTaipeiTaiwan
- Clinical Big Data Research CenterTaipei Medical University Hospital, Taipei Medical UniversityTaipeiTaiwan
- Research Center of Health Care Industry Data Science, College of ManagementTaipei Medical UniversityTaipeiTaiwan
| | - Whitney Burton
- International Ph.D. Program in Biotech and Healthcare Management, College of ManagementTaipei Medical UniversityTaipeiTaiwan
| | | | - Weei‐Chin Lin
- Section of Hematology/Oncology, Department of Medicine and Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTexasUSA
| | - Christine Y. Lu
- Department of Population MedicineHarvard Medical School and Harvard Pilgrim Health Care InstituteBostonMassachusettsUSA
- Kolling Institute, Faculty of Medicine and HealthThe University of Sydney and the Northern Sydney Local Health DistrictSydneyNew South WalesAustralia
- School of Pharmacy, Faculty of Medicine and HealthThe University of SydneySydneyNew South WalesAustralia
| | - Min‐Huei Hsu
- Clinical Data Center, Office of Data ScienceTaipei Medical UniversityTaipeiTaiwan
- Graduate Institute of Data Science, College of ManagementTaipei Medical UniversityTaipeiTaiwan
| | - Chi‐Tsun Cheng
- Research Center of Health Care Industry Data Science, College of ManagementTaipei Medical UniversityTaipeiTaiwan
| | - Jason C. Hsu
- International Ph.D. Program in Biotech and Healthcare Management, College of ManagementTaipei Medical UniversityTaipeiTaiwan
- Clinical Data Center, Office of Data ScienceTaipei Medical UniversityTaipeiTaiwan
- Clinical Big Data Research CenterTaipei Medical University Hospital, Taipei Medical UniversityTaipeiTaiwan
- Research Center of Health Care Industry Data Science, College of ManagementTaipei Medical UniversityTaipeiTaiwan
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17
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Di Donato M, Medici N, Migliaccio A, Castoria G, Giovannelli P. Exosomes: Emerging Modulators of Pancreatic Cancer Drug Resistance. Cancers (Basel) 2023; 15:4714. [PMID: 37835408 PMCID: PMC10571735 DOI: 10.3390/cancers15194714] [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: 08/10/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
Pancreatic cancer (PaC) is one of the most lethal tumors worldwide, difficult to diagnose, and with inadequate therapeutical chances. The most used therapy is gemcitabine, alone or in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the multidrug FOLFIRINOX. Unfortunately, PaC develops resistance early, thus reducing the already poor life expectancy of patients. The mechanisms responsible for drug resistance are not fully elucidated, and exosomes seem to be actively involved in this phenomenon, thanks to their ability to transfer molecules regulating this process from drug-resistant to drug-sensitive PaC cells. These extracellular vesicles are released by both normal and cancer cells and seem to be essential mediators of intercellular communications, especially in cancer, where they are secreted at very high numbers. This review illustrates the role of exosomes in PaC drug resistance. This manuscript first provides an overview of the pharmacological approaches used in PaC and, in the last part, focuses on the mechanisms exploited by the exosomes released by cancer cells to induce drug resistance.
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Affiliation(s)
| | | | | | | | - Pia Giovannelli
- Department of Precision Medicine, University of Campania “L.Vanvitelli”, Via L. De Crecchio 7, 80138 Naples, Italy
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18
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Koltai T. Earlier Diagnosis of Pancreatic Cancer: Is It Possible? Cancers (Basel) 2023; 15:4430. [PMID: 37760400 PMCID: PMC10526520 DOI: 10.3390/cancers15184430] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/31/2023] [Accepted: 08/06/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires C1094, Argentina
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19
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Zuberi SA, Shah I, Bocchino RL, Ahmed A, Freedman SD, Kothari DJ, Sheth SG. Pre-existing, Concurrent/Early-Onset, and Late-Onset Diabetes in Chronic Pancreatitis: Do Outcomes Differ? Dig Dis Sci 2023; 68:1519-1524. [PMID: 36318379 DOI: 10.1007/s10620-022-07742-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/17/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND/AIMS Diabetes secondary to endocrine insufficiency in chronic pancreatitis (CP) may develop at any time during the disease course. We sought to evaluate the differences in clinical characteristics and outcomes in CP patients with pre-existing, early-onset, and late-onset diabetes. METHODS We reviewed CP patients seen at our Pancreas Center during 2016-2021. We divided them into four groups: those without diabetes, with pre-existing diabetes, with early-onset diabetes, and with late-onset diabetes. We then compared clinical characteristics and outcomes. RESULTS We identified 450 patients with CP: 271 without diabetes, 99 with pre-existing diabetes, 51 with early-onset diabetes, and 29 with late-onset diabetes. Early-onset diabetics were younger (54.1 vs 57.3 vs 62.5 vs 61.9 years), had more alcohol-related CP (45.1% vs 31.7% vs 32.3% vs 31%), had higher HbA1C levels (8.02% vs 5.11% vs 7.71% vs 7.66%), were more likely to be on insulin (78.4% vs 0% vs 48.4% vs 65.5%), and used more opioids (64.7% vs 43.9% vs 55.1% vs 44.8%) and gabapentinoids (66.7% vs 43.5% vs 48% vs 60.7%) compared to other groups (p < 0.05). Patients who developed diabetes after CP diagnosis had more exocrine insufficiency (72.4% vs 70.6% vs 65.7% vs 53.1%), anatomical complications, and interventions for pain control (p < 0.05). There was no difference in pancreatic cancer in the four groups. CONCLUSION CP patients who are younger and use alcohol are at higher risk of having early-onset diabetes and have poorer glucose control compared other CP patients. Patients who develop diabetes after CP diagnosis have worse outcomes and use more resources.
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Affiliation(s)
- Shaharyar A Zuberi
- Department of Internal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
| | - Ishani Shah
- Division of Gastroenterology, Department of Internal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA
| | - Rachel L Bocchino
- Department of Internal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
| | - Awais Ahmed
- Division of Gastroenterology, Department of Internal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA
| | - Steven D Freedman
- Division of Gastroenterology, Department of Internal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA
| | - Darshan J Kothari
- Division of Gastroenterology, Department of Internal Medicine, Duke University Medical Center, Durham, NC, USA
| | - Sunil G Sheth
- Division of Gastroenterology, Department of Internal Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA.
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Mikolaskova I, Crnogorac-Jurcevic T, Smolkova B, Hunakova L. Nutraceuticals as Supportive Therapeutic Agents in Diabetes and Pancreatic Ductal Adenocarcinoma: A Systematic Review. BIOLOGY 2023; 12:158. [PMID: 36829437 PMCID: PMC9953002 DOI: 10.3390/biology12020158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023]
Abstract
The correlation between pancreatic ductal adenocarcinoma (PDAC) and diabetes-related mechanisms support the hypothesis that early therapeutic strategies targeting diabetes can contribute to PDAC risk reduction and treatment improvement. A systematic review was conducted, using PubMed, Embase and Cochrane Library databases, to evaluate the current evidence from clinical studies qualitatively examining the efficacy of four natural products: Curcumin-Curcuma longa L.; Thymoquinone-Nigella sativa L.; Genistein-Glycine max L.; Ginkgo biloba L.; and a low-carbohydrate ketogenic diet in type 2 diabetes (T2D) and PDAC treatment. A total of 28 clinical studies were included, showing strong evidence of inter-study heterogeneity. Used as a monotherapy or in combination with chemo-radiotherapy, the studied substances did not significantly improve the treatment response of PDAC patients. However, pronounced therapeutic efficacy was confirmed in T2D. The natural products and low-carbohydrate ketogenic diet, combined with the standard drugs, have the potential to improve T2D treatment and thus potentially reduce the risk of cancer development and improve multiple biological parameters in PDAC patients.
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Affiliation(s)
- Iveta Mikolaskova
- Institute of Immunology, Faculty of Medicine, Comenius University, Odborarske Namestie 14, 811 08 Bratislava, Slovakia
| | - Tatjana Crnogorac-Jurcevic
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, Charterhouse Square, London EC1M 6BQ, UK
| | - Bozena Smolkova
- Biomedical Research Center, Slovak Academy of Sciences, Cancer Research Institute, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Luba Hunakova
- Institute of Immunology, Faculty of Medicine, Comenius University, Odborarske Namestie 14, 811 08 Bratislava, Slovakia
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21
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Sugar Sweetened and Artificially Sweetened Beverage Consumption and Pancreatic Cancer: A Retrospective Study. Nutrients 2023; 15:nu15020275. [PMID: 36678146 PMCID: PMC9866356 DOI: 10.3390/nu15020275] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/15/2022] [Accepted: 12/31/2022] [Indexed: 01/06/2023] Open
Abstract
Pancreatic cancer (PanCa) is a highly fatal malignancy with few modifiable risk and prognostic factors. This study investigates the association between cola, diet cola, and non-cola soft drink consumption and PanCa risk and mortality. A retrospective study was conducted using data from the Patient Epidemiology Data System (1982-1998) at Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA), including 213 PanCa patients and 852 cancer-free controls. Data were collected using a self-administered questionnaire, including a 46-item food frequency questionnaire (FFQ). Multivariable logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) of cola, diet cola, and non-cola soft drink consumption and PanCa risk. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CIs of cola, diet cola, and non-cola soft drink consumption and PanCa mortality. Stratified analyses were conducted by sex, body mass index (BMI), and smoking status. We observed significant 55% increased odds of PanCa among patients consuming ≥1 regular cola per day (OR: 1.55, 95% CI: 1.01-2.39). We also observed non-significant 38% increased hazard of mortality among patients consuming ≥1 regular cola per day (HR: 1.38, 95% CI: 0.91-2.07). We conclude that regular cola consumption is a modifiable lifestyle that may be associated with PanCa risk and mortality following diagnosis.
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22
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Koo DH, Han K, Park CY. Impact of cumulative hyperglycemic burden on the pancreatic cancer risk: A nationwide cohort study. Diabetes Res Clin Pract 2023; 195:110208. [PMID: 36513269 DOI: 10.1016/j.diabres.2022.110208] [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: 08/28/2022] [Revised: 11/23/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
AIMS We aimed to investigate how much cumulative hyperglycemia exposure increases pancreatic cancer risk. METHODS This study used the National Health Insurance Service Database of Claims and included 3,138,099 individuals who underwent four consecutive annual health screenings between 2009 and 2013. We defined hyperglycemic burden in two ways. First, the hyperglycemic burden was given a score from 0 to 4, with one point assigned for each time blood glucose was ≥100 mg/dL or the use of an antidiabetic drug. Furthermore, we performed semiquantitative scoring of a pre-diabetic (100-125; 1 point) and diabetic level (≥126; 2 points) and categorized into one of nine groups (hyperglycemic score 0-8). RESULTS During the median 6.2 years of follow-up, groups with a hyperglycemic burden of 1, 2, 3, and 4 had a 15%, 30%, 26%, and 67% increased pancreatic cancer risk compared with normal subjects. In semiquantitative analyses, individuals with a pre-diabetic glucose level on at least one occasion had a 14% increased the risk. Furthermore, individuals with a burden score of 8 had an 89% higher risk than subjects with a normal range. CONCLUSIONS The pancreatic cancer incidence increased significantly according to the hyperglycemic burden, defined as sustained hyperglycemic exposure, including pre-diabetic levels.
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Affiliation(s)
- Dong-Hoe Koo
- Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, South Korea
| | - Cheol-Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea.
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Kim Y, Koh JS, Woo SD, Lee SI, Kang DH, Park D, Chung C, Kwon IS, Lee JE. The Tri-iodothyronine (T3) Level Is a Prognostic Factor for Patients With Advanced NSCLC: Receiving Immune Checkpoint Inhibitors and Is Associated With Liver Metastasis. Clin Med Insights Oncol 2022; 16:11795549221139522. [PMID: 36532699 PMCID: PMC9751177 DOI: 10.1177/11795549221139522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/01/2022] [Indexed: 08/22/2023] Open
Abstract
BACKGROUND Endocrine hormones influence tumor progression and the response to treatment. Despite the importance of immune checkpoint inhibitors (ICIs) as treatments for advanced non-small cell lung cancer (NSCLC), few studies have explored the effects of hormone levels in NSCLC patients on the effectiveness of ICI therapies. We thus investigated the effects of baseline blood markers in patients with advanced NSCLC on ICI treatments. METHODS Patients with advanced NSCLC who received programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors at Chungnam National University Hospital between December 2016 and November 2020 and who lacked any history of thyroid gland-related diseases were analyzed retrospectively. We collected clinical information and baseline laboratory data, including the levels of endocrine hormones, cytokines, complete blood counts (CBCs), and peripheral blood chemistry panels. We explored the relationships of hormone levels with clinical outcomes (overall survival [OS], progression-free survival [PFS], and best response), liver metastasis, and blood markers using the Kaplan-Meier method, Cox's proportional hazards regression, and logistic regression. RESULTS A total of 113 patients were enrolled. A shorter PFS was independently associated with liver metastasis, higher cortisol levels, and lower hemoglobin (Hb) levels; a shorter OS was associated with liver metastasis, lower tri-iodothyronine (T3) levels, higher lactate dehydrogenase (LDH) levels, and lower albumin levels. Patients with low T3 levels exhibited a shorter PFS and OS, and a poorer best response. Patients with low T3 levels tended to have higher disease progression rates, lower levels of adrenocorticotropic hormone (ACTH), C-peptide, albumin, Hb, and neutrophil-to-lymphocyte ratio, and higher levels of interleukin (IL)-6, white blood cells, platelets, compared with those with normal T3 levels. We found a significant association between a low T3 level and liver metastasis. CONCLUSIONS We found the baseline T3 level was associated with both prognosis and the response to ICIs in patients with advanced NSCLC, probably reflecting impaired liver function and systemic inflammation induced by the interaction of T3 with other biomarkers, such as IL-6, ACTH, cortisol, C-peptide, Hb, LDH, and albumin.
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Affiliation(s)
- Yoonjoo Kim
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Jeong Suk Koh
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Seong-Dae Woo
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Song-I Lee
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Da Hyun Kang
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Dongil Park
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Chaeuk Chung
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - In-Sun Kwon
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Jeong Eun Lee
- Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
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Wu S, Zhang H, Gao C, Chen J, Li H, Meng Z, Bai J, Shen Q, Wu H, Yin T. Hyperglycemia Enhances Immunosuppression and Aerobic Glycolysis of Pancreatic Cancer Through Upregulating Bmi1-UPF1-HK2 Pathway. Cell Mol Gastroenterol Hepatol 2022; 14:1146-1165. [PMID: 35863742 PMCID: PMC9606831 DOI: 10.1016/j.jcmgh.2022.07.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/09/2022] [Accepted: 07/11/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Accumulating evidence strongly suggests that hyperglycemia promotes the progression of pancreatic cancer (PC). Approximately 80% of patients with PC are intolerant to hyperglycemic conditions. In this study, we define the role of Bmi1, a stemness-related oncogene, in controlling the Warburg effect, and immune suppression under hyperglycemia conditions. METHODS The diabetes mellitus model was established by intraperitoneal injection of streptozotocin. The role of the hyperglycemia-Bmi1-HK2 axis in glycolysis-related immunosuppression was examined in both orthotopic and xenograft in vivo models. Evaluation of immune infiltrates was carried out by flow cytometry. Human PC cell lines, SW1990, BxPC-3, and CFPAC-1, were used for mechanistic in vitro studies. RESULTS Through bioinformatics analysis, we found that hyperglycemia was strongly related to aerobic glycolysis, immunosuppression, and cancer cell stemness. High glucose condition in the tumor microenvironment promotes immune suppression by upregulating glycolysis in PC cells, which can be rescued via knockdown Bmi1 expression or after 2-deoxy-D-glucose treatment. Through gain-/loss-of-function assessments, we found that Bmi1 upregulated the expression of UPF1, which enhanced the stability of HK2 mRNA and thereby increased the expression of HK2. The role of the hyperglycemia-Bmi-HK2 pathway in the inhibition of antitumor immunity was further verified via the immune-competent and immunodeficient mice model. We also demonstrated that hyperglycemia promotes the expression of Bmi1 by elevating the intracellular acetyl-CoA levels and histone H4 acetylation levels. CONCLUSIONS Our results suggest that the previously unreported Bmi1-UPF1-HK2 pathway contributes to PC progression and immunosuppression, which may bring in new targets for developing effective therapies to treat patients with PC.
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Affiliation(s)
- Shihong Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haoxiang Zhang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenggang Gao
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaoshun Chen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hehe Li
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zibo Meng
- Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany
| | - Jianwei Bai
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiang Shen
- Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Heshui Wu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Yin
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,Correspondence Address correspondence to: Tao Yin, MD, PhD, Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Tel: +86 027-85351631.
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George S, Jean-Baptiste W, Yusuf Ali A, Inyang B, Koshy FS, George K, Poudel P, Chalasani R, Goonathilake MR, Waqar S, Mohammed L. The Role of Type 2 Diabetes in Pancreatic Cancer. Cureus 2022; 14:e26288. [PMID: 35898377 PMCID: PMC9308974 DOI: 10.7759/cureus.26288] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/24/2022] [Indexed: 11/05/2022] Open
Abstract
The incidence of type 2 diabetes mellitus (T2DM) and its potential complications, such as cancers, are increasing worldwide at an astounding rate. There are many factors such as obesity, diabetes, alcohol consumption, and the adoption of sedentary lifestyles that are driving pancreatic cancer (PC) to become one of the leading causes of cancer mortality in the United States. PC is notorious for its generic symptoms and late-stage presentation with rapid metastasis. The connection between T2DM and the risk of PC development is multifaceted and complex. Some of the proposed theories reveal that chronic inflammation, insulin resistance, hyperinsulinemia, hyperglycemia, and abnormalities in the insulin and insulin-like growth factor axis (IGF) contribute to the disease association between these two conditions. This literature review aims to highlight relevant studies and explore the molecular mechanisms involved in the etiology of diabetes and its impact on PC development, as well as the role of anti-diabetic agents on PC. Despite extensive studies, the exact interaction between T2DM and PC remains obscure and will need further investigation. According to current knowledge, there is a substantial link between diabetes, obesity, and dietary patterns in the development and progression of PC. Consequently, focusing our efforts on preventive measures by reducing modifiable risk factors remains the most effective strategy to reduce the risk of PC at this time. Antidiabetic drugs can have various effects on the occurrence and prognosis of PC with metformin offering a clear benefit of inhibiting PC and insulin increasing the risk of PC. The development of future novel therapies will require a deeper knowledge of the triggering mechanisms and interplay between these two disease states.
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Annular-shaped stenosis in the ureter: Caution should be taken. Urol Oncol 2022; 40:274.e7-274.e14. [DOI: 10.1016/j.urolonc.2022.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/27/2022] [Indexed: 11/17/2022]
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Dirweesh A, Trikudanathan G, Freeman ML. Endoscopic Management of Complications in Chronic Pancreatitis. Dig Dis Sci 2022; 67:1624-1634. [PMID: 35226223 DOI: 10.1007/s10620-022-07391-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/04/2022] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW Management of complications in patients with chronic pancreatitis is often suboptimal. This review discusses detailed endoscopic approaches for managing complications in CP. LITERATURE FINDINGS CP is characterized by progressive and irreversible destruction of pancreatic parenchyma and ductal system resulting in fibrosis, scarring, and loss of glandular function. Abdominal pain remains is the most common symptom of the disease and the main aim of medical, endoscopic, and surgical therapy is to help relieve symptoms, prevent disease progression, and manage complications related to CP. In fact, advances in our understanding of CP have improved medical care and quality of life in these patients. With significant sequela, morbidity and a progressive nature, a thorough understanding of the pathophysiology, natural course, diagnostic approaches, and optimal management strategies for this disease is warranted. The existing modalities and new innovations in this field are safe, effective, and likely to have a positive impact on management of complication in CP whenever used in the right context.
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Affiliation(s)
- Ahmed Dirweesh
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, MMC 36, 420 Delaware St SE, Minneapolis, MN, 55455, USA
| | - Guru Trikudanathan
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, MMC 36, 420 Delaware St SE, Minneapolis, MN, 55455, USA
| | - Martin L Freeman
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, MMC 36, 420 Delaware St SE, Minneapolis, MN, 55455, USA.
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Brewer MJ, Doucette JT, Bar-Mashiah A, Glickman JW, Kessel E, Aronson A, Lucas AL. Glycemic Changes and Weight Loss Precede Pancreatic Ductal Adenocarcinoma by up to 3 Years in a Diverse Population. Clin Gastroenterol Hepatol 2022; 20:1105-1111.e2. [PMID: 34358720 DOI: 10.1016/j.cgh.2021.07.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/20/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Elevations in fasting blood glucose are observed prior to the development of pancreatic ductal adenocarcinoma (PDAC). Our aim was to describe glycemic and weight changes that occur prior to PDAC diagnosis in a diverse population. METHODS We conducted a case-control study comparing patients with PDAC with matched controls between January 2011 and November 2019 at a tertiary care institution. Normally distributed variables were compared using t tests, and the Wilcoxon rank sum test was used for non-normally distributed variables; logistic regression was used to estimate odds of PDAC based on changes over time in hemoglobin A1c (HbA1c) and body mass index (BMI), controlling for appropriate confounders. RESULTS A total of 4626 patients met inclusion criteria: 1542 cases and 3084 controls; the median age was 69.3 years, and 2487 (53.8%) were male; 751 cases (48.7%) were non-Hispanic white. In the 3 years prior to diagnosis, HbA1c was higher in patients with PDAC compared with controls (P ≤ .02 for all); a similar trend was seen for glucose values. BMI was greater for patients with PDAC for all study periods, except 0 to 6 months prior to cancer diagnosis when BMI was lower (P < .01 for all). The change in BMI (ΔBMI) of cases at 1 year and 6 months before diagnosis was -0.59 and -1.21 when compared with -0.08 and 0.03 for controls (P < .01 for both). Multivariable logistic regression demonstrated that HbA1c slope (adjusted odds ratio, 1.33; 95% confidence interval, 1.01-1.76) and BMI slope (adjusted odds ratio, 0.75; 95% confidence interval, 0.65-0.87) were predictors of PDAC. CONCLUSION Glycemic elevations and weight loss predate PDAC diagnosis. These metabolic changes may suggest an underlying PDAC.
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Affiliation(s)
- Marlon J Brewer
- Henry D. Janowitz Division of Gastroenterology, New York, New York
| | - John T Doucette
- Division of Biostatistics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ariel Bar-Mashiah
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Jacob W Glickman
- Henry D. Janowitz Division of Gastroenterology, New York, New York
| | - Elizabeth Kessel
- Henry D. Janowitz Division of Gastroenterology, New York, New York
| | - Anne Aronson
- Henry D. Janowitz Division of Gastroenterology, New York, New York
| | - Aimee L Lucas
- Henry D. Janowitz Division of Gastroenterology, New York, New York.
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Bao J, Liu D, Sun J, Su X, Cheng H, Qi L, Zhang Y, Lv Y, Ye Z, Yu X, Wei Q, Qiu Y, Su J, Li L. Pancreatic cancer-associated diabetes mellitus is characterized by reduced β-cell secretory capacity, rather than insulin resistance. Diabetes Res Clin Pract 2022; 185:109223. [PMID: 35149166 DOI: 10.1016/j.diabres.2022.109223] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/19/2021] [Accepted: 01/28/2022] [Indexed: 11/24/2022]
Abstract
AIMS The early distinction of pancreatic cancer associated diabetes (PaCDM) in patients with elderly diabetes is critical. However, PaCDM and type 2 diabetes mellitus (T2DM) remain indistinguishable. We aim to address the differences between the pancreatic and gut endocrine hormones of patients with PaCDM and T2DM. METHODS A total of 44 participants underwent mixed meal tolerance test (MMTT). Fasting and postprandial concentrations of insulin, C-peptide, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) were measured. Insulin sensitivity and secretion indices were calculated. One-way ANOVA with post-hoc analysis was used for statistical analysis. RESULTS Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared with T2DM. Baseline concentrations and AUCs differed. PaCDM patients showed lower insulin secretion capacity but better insulin sensitivity than T2DM patients. The peak concentration and AUC of PP in T2DM group were higher than healthy controls, but in accordance with PaCDM. PaCDM patients presented lower baseline GLP-1 concentration than T2DM patients. No between-group differences were found for glucagon and GIP. CONCLUSIONS PaCDM patients had a lower baseline and postprandial insulin and C-peptide secretion than T2DM patients. Reduced insulin secretion and improved peripheral sensitivity were found in PaCDM patients compared with T2DM.
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Affiliation(s)
- Jiantong Bao
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Dechen Liu
- Department of Endocrinology, School of Medicine, and Department of Clinical Science and Research, Zhongda Hospital, Southeast University, Nanjing, China
| | - Jinfang Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
| | - Xianghui Su
- Department of Endocrinology, Changji Branch, First Affiliated Hospital of Xinjiang Medical University, Xinjiang 831100, China
| | - Hao Cheng
- Department of Hepatobiliary and Pancreatic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yidi Zhang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yingqi Lv
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zheng Ye
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xuebing Yu
- Department of Endocrinology, Changzhou Jintan District People's Hospital, School of Medicine in Jiangsu University, Changzhou, China
| | - Qiong Wei
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yudong Qiu
- Department of Hepatobiliary and Pancreatic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jianhua Su
- Changzhou Jintan District People's Hospital, School of Medicine in Jiangsu University, Changzhou, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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Talib WH, Mahmod AI, Abuarab SF, Hasen E, Munaim AA, Haif SK, Ayyash AM, Khater S, AL-Yasari IH, Kury LTA. Diabetes and Cancer: Metabolic Association, Therapeutic Challenges, and the Role of Natural Products. Molecules 2021; 26:2179. [PMID: 33920079 PMCID: PMC8070467 DOI: 10.3390/molecules26082179] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer is considered the second leading cause of death worldwide and in 2018 it was responsible for approximately 9.6 million deaths. Globally, about one in six deaths are caused by cancer. A strong correlation was found between diabetes mellitus and carcinogenesis with the most evident correlation was with type 2 diabetes mellitus (T2DM). Research has proven that elevated blood glucose levels take part in cell proliferation and cancer cell progression. However, limited studies were conducted to evaluate the efficiency of conventional therapies in diabetic cancer patients. In this review, the correlation between cancer and diabetes will be discussed and the mechanisms by which the two diseases interact with each other, as well as the therapeutics challenges in treating patients with diabetes and cancer with possible solutions to overcome these challenges. Natural products targeting both diseases were discussed with detailed mechanisms of action. This review will provide a solid base for researchers and physicians to test natural products as adjuvant alternative therapies to treat cancer in diabetic patients.
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Affiliation(s)
- Wamidh H. Talib
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Asma Ismail Mahmod
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Sara Feras. Abuarab
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Eliza Hasen
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Amer A. Munaim
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Shatha Khaled Haif
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Amani Marwan Ayyash
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Samar Khater
- Department of Clinical Pharmacy and Therapeutic, Applied Science Private University, Amman 11931-166, Jordan; (A.I.M.); (S.F.A.); (E.H.); (A.A.M.); (S.K.H.); (A.M.A.); (S.K.)
| | - Intisar Hadi AL-Yasari
- Department of Genetic Engineering, College of Biotechnology, Al-Qasim Green University, Babylon 00964, Iraq;
| | - Lina T. Al Kury
- Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, United Arab Emirates;
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Abstract
ABSTRACT Microorganisms can help maintain homeostasis in humans by providing nutrition, maintaining hormone balance, and regulating inflammatory responses. In the case of imbalances, these microbes can cause various diseases, even malignancy. Pancreatic cancer (PC) is characterized by high tumor invasiveness, distant metastasis, and insensitivity to traditional chemotherapeutic drugs, and it is confirmed that PC is closely related to microorganisms. Recently, most studies based on clinical samples or case reports discussed the positive or negative relationships between microorganisms and PC. However, the specific mechanisms are blurry, especially the involved immunological pathways, and the roles of beneficial flora have usually been ignored. We reviewed studies published through September 2020 as identified using PubMed, MEDLINE, and Web of Science. We mainly introduced the traits of oral, gastrointestinal, and intratumoral microbes in PC and summarized the roles of these microbes in tumorigenesis and tumoral development through immunological pathways, in addition to illustrating the relationships between metabolic diseases with PC by microorganism. In addition, we identified microorganisms as biomarkers for early diagnosis and immunotherapy. This review will be significant for greater understanding the effect of microorganisms in PC and provide more meaningful guidance for future clinical applications.
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Affiliation(s)
- Xin Wei
- From the Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun
| | - Chunlei Mei
- Institute of Reproductive Health, Huazhong University of Science and Technology, Wuhan, China
| | - Xixi Li
- From the Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun
| | - Yingjun Xie
- From the Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun
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Sütő G, Molnár GA, Rokszin G, Fábián I, Kiss Z, Szekanecz Z, Poór G, Jermendy G, Kempler P, Wittmann I. Risk of morbidity and mortality in patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor and/or dipeptidyl peptidase-4 inhibitor: a nationwide study. BMJ Open Diabetes Res Care 2021; 9:9/1/e001765. [PMID: 33472796 PMCID: PMC7818813 DOI: 10.1136/bmjdrc-2020-001765] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/12/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Mortality and disability in diabetes mellitus are determined mostly by cardiovascular complications and cancer. The impact of dipeptidyl peptidase-4 inhibitor (DPP-4i) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) monotherapy or combination on long-term complications of type 2 diabetes mellitus was studied. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes treated with DPP-4i or SGLT2i during a 3-year period were identified in the database of the National Institute of Health Insurance Fund in Hungary. All-cause mortality, acute myocardial infarction, stroke, hospitalization for heart failure (HHF), lower limb amputation (LLA) and cancer were assessed. Outcomes of add-on SGLT2i to DPP-4i treatment in comparison with switching DPP-4i therapy to SGLT2i were also evaluated. After propensity score matching, survival analysis was performed with a Cox proportional hazards model. RESULTS After propensity score matching, both SGLT2i and DPP-4i groups included 18 583 patients. All-cause mortality (HR, 0.80; 95% CI 0.68 to 0.94; p=0.0057), HHF (HR, 0.81; 95% CI 0.71 to 0.92; p=0.0018), and risk of cancer (HR, 0.75; 95% CI 0.66 to 0.86; p<0.0001) were lower in the SGLT2i population compared with DPP-4i. Risk of LLA was higher in the SGLT2i group (HR, 1.35; 95% CI 1.03 to 1.77; p=0.0315). SGLT2i in combination with DPP-4i results in lower all-cause mortality (HR, 0.46; 95% CI 0.31 to 0.67; p=0.0001), with a lower trend in stroke, LLA, HHF and cancer, but without any statistical difference. CONCLUSIONS SGLT2i treatment leads to a lower risk of overall mortality, HHF and cancer when compared with DPP-4i treatment. Adding SGLT2i to DPP-4i instead of switching from DPP-4i to SGLT2i further lowers the risk of all-cause mortality.
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Affiliation(s)
- Gábor Sütő
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Gergő A Molnár
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | | | | | - Zoltan Kiss
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gyula Poór
- National Institute of Rheumatology and Physiotherapy, Budapest, Hungary
| | | | - Peter Kempler
- First Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - István Wittmann
- Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs Medical School, Pécs, Hungary
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Barcellini A, Peloso A, Pugliese L, Vitolo V, Cobianchi L. Locally Advanced Pancreatic Ductal Adenocarcinoma: Challenges and Progress. Onco Targets Ther 2020; 13:12705-12720. [PMID: 33335406 PMCID: PMC7737010 DOI: 10.2147/ott.s220971] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/30/2020] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the major causes of death in the Western world, and it is estimated to become the second leading cause of tumour-related mortality in the next 10 years. Among pancreatic cancers, ductal adenocarcinomas are by far the most common, characterised by a challenging diagnosis due to the lack of initial and pathognomonic clinical signs. In this scenario, non-metastatic locally advanced pancreatic cancer (LAPC) accounts for a large proportion of all new pancreatic ductal adenocarcinoma diagnoses. There is no consensus on a common definition of LAPC. Still, it usually includes tumours that are not resectable due to vascular involvement. As of today, treatment is limited, and the prognosis is very unfavourable. Curative-intent surgery remains the gold-standard even if often jeopardized by vascular involvement. Continuing progress in our understanding of LAPC genetics and immunology will permit the development of different treatments, targeted or combined, including radiation therapy, hadrontherapy, targeted immunotherapies or new chemotherapies. A multidisciplinary approach combining various fields of expertise is essential in aiming to limit disease progression as well as patient outcome. Using a narrative literature review approach, the manuscript explores the most up-to-date knowledge concerning locally advanced pancreatic ductal adenocarcinoma management.
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Affiliation(s)
- Amelia Barcellini
- National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy
| | - Andrea Peloso
- Divisions of Transplantation and Visceral Surgery, Department of Surgery, University of Geneva, Geneva, Switzerland
| | - Luigi Pugliese
- General Surgery, Foundation IRCCS San Matteo Hospital, Pavia, Italy
| | - Viviana Vitolo
- National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy
| | - Lorenzo Cobianchi
- General Surgery, Foundation IRCCS San Matteo Hospital, Pavia, Italy.,Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, Foundation IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy
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Ahn HK, Lee YH, Koo KC. Current Status and Application of Metformin for Prostate Cancer: A Comprehensive Review. Int J Mol Sci 2020; 21:ijms21228540. [PMID: 33198356 PMCID: PMC7698147 DOI: 10.3390/ijms21228540] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/31/2020] [Accepted: 11/09/2020] [Indexed: 12/15/2022] Open
Abstract
Metformin, an oral biguanide used for first-line treatment of type 2 diabetes mellitus, has attracted attention for its anti-proliferative and anti-cancer effects in several solid tumors, including prostate cancer (PCa). Liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) activation, inhibition of the mammalian target of rapamycin (mTOR) activity and protein synthesis, induction of apoptosis and autophagy by p53 and p21, and decreased blood insulin level have been suggested as direct anti-cancer mechanisms of metformin. Research has shown that PCa development and progression are associated with metabolic syndrome and its components. Therefore, reduction in the risk of PCa and improvement in survival in metformin users may be the results of the direct anti-cancer mechanisms of the drug or the secondary effects from improvement of metabolic syndrome. In contrast, some research has suggested that there is no association between metformin use and PCa incidence or survival. In this comprehensive review, we summarize updated evidence on the relationship between metformin use and oncological effects in patients with PCa. We also highlight ongoing clinical trials evaluating metformin as an adjuvant therapy in novel drug combinations in various disease settings.
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Farias AJ, Wu AH, Porcel J, Marchand LL, Wilkens LR, Monroe KR, Maskarinec G, Pandol SJ, Setiawan VW. Diabetes-Related Complications and Pancreatic Cancer Incidence in the Multiethnic Cohort. JNCI Cancer Spectr 2020; 4:pkaa035. [PMID: 33134820 PMCID: PMC7583154 DOI: 10.1093/jncics/pkaa035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/23/2020] [Accepted: 04/24/2020] [Indexed: 12/19/2022] Open
Abstract
Background People with diabetes are at an increased risk of developing pancreatic cancer. However, it is unclear whether diabetes-related complications are associated with risk of pancreatic cancer. Methods A nested matched case-control analysis was conducted among the fee-for-service Medicare participants of the prospective Multiethnic Cohort (n = ∼123 000). Between 2001 and 2014, 433 incident cases of pancreatic ductal adenocarcinoma were matched to 1728 controls by birth year, sex, race and ethnicity, and age at cohort entry. Participants were linked to data from the California and Hawaii cancer registries and Medicare claims. We used the diabetes complications severity index (DCSI) for the presence of 7 complications within 2 years prior to the diagnosis date of the index case. Multivariable conditional logistic regression was used to examine the association of DCSI with pancreatic cancer incidence. Results Diabetes was present among 45.4% of cases and 34.1% of controls. Cases had higher DCSI score compared with controls (score ≥4: 32.8% in cases; 21.2% in controls). The most prevalent diabetes-related complications for cases were cardiovascular disease (61.2%), nephropathy (31.2%), and cerebrovascular disease (21.7%). Individuals with diabetes (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.14 to 1.91), nephropathy (OR = 1.75, 95% CI = 1.32 to 2.33), cardiovascular disease (OR = 1.88, 95% CI = 1.45 to 2.44), and metabolic complications (OR = 6.61, 95% CI = 2.49 to 17.50) were at increased risk of pancreatic cancer. For every 1-unit increase in DCSI score, participants had 18% greater risk of pancreatic cancer (OR = 1.18, 95% CI = 1.11 to 1.25). Conclusions Participants with diabetes-related complications have an elevated risk of pancreatic cancer. Identifying diabetes-related complications may help identify high-risk groups who can be studied for development of early markers for this fatal cancer.
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Affiliation(s)
- Albert J Farias
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Jacqueline Porcel
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Lynne R Wilkens
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Kristine R Monroe
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Stephen J Pandol
- Division of Gastroenterology, Departments of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Veronica Wendy Setiawan
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.,Norris Comprehensive Cancer Center, Los Angeles, CA, USA
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Tavano F, Fontana A, Mazza T, Gioffreda D, Biagini T, Palumbo O, Carella M, Andriulli A. Early-Onset Diabetes as Risk Factor for Pancreatic Cancer: miRNA Expression Profiling in Plasma Uncovers a Role for miR-20b-5p, miR-29a, and miR-18a-5p in Diabetes of Recent Diagnosis. Front Oncol 2020; 10:1567. [PMID: 33072549 PMCID: PMC7533599 DOI: 10.3389/fonc.2020.01567] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
The high prevalence of early-diabetes in patients with pancreatic cancer (PanC) implies that its recognition could help identify people at high risk of developing PanC. Candidate microRNAs (miRNAs) associated with recent diabetes were screened from our previous miRNA expression profiling on 10 pools of plasma from PanC patients and non-PanC controls, both including also subjects with early- and late-diabetes. The droplet digital PCR (ddPCR) was used to re-test candidate miRNAs in a new independent cohort of 69 subjects (40 PanC, 29 non-PanC) with early- (17 PanC, 13 non-PanC) or late-diabetes (23 PanC, 16 non-PanC), and in 100 non-diabetic healthy subjects (HS). miRNA levels were evaluated for differences between subjects enrolled into the study and for their diagnostic performance, also compared to the CA 19-9 determinations. MiR-20b-5p, miR-29a, and miR-18a-5p were selected from the previous miRNA expression profiling. The ddPCR confirmed the increase of miR-20b-5p and miR-29a levels in PanC with early- compared to those with late-diabetes. Conversely, miR-20b-5p, miR-29a, and miR-18a-5p were over-expressed in both PanC and non-PanC with recent diabetes compared to HS, and each miRNA achieved a similar diagnostic performance in distinguishing either PanC or non-PanC with early-diabetes from HS (miR-20b-5p: AUC = 0.877 vs. AUC = 0.873; miR-29a: AUC = 0.838 vs. AUC = 0.810; miR-18a-5p: AUC = 0.824 vs. AUC = 0.875). Despite miR-20b-5p and miR-29a expressions were also higher both in PanC and non-PanC with late-diabetes with respect to HS, the diagnostic accuracy in PanC with late-diabetes vs. HS reached by each miRNA (miR-20b-5p: AUC = 0.760; miR-29a: AUC = 0.630) was lower than the ones achieved in PanC with early-diabetes vs. HS. Furthermore, miR-20b-5p achieved a higher diagnostic accuracy to discriminate non-PanC with early-diabetes from HS (AUC = 0.868; SP = 81%; PPV = 32.1%) compared to the CA 19-9 (AUC = 0.700; SP = 40.0%; PPV = 15.5%), and the joint (miR-20b-5p and CA 19-9) discrimination ability was higher than the one achieved by the CA 19-9 tested alone (AUC = 0.900, p = 0.003). Our data highlighted the association between miR-18a-5p and early-diabetes, and suggested for miR-20b-5p and miR-29 a role in identifying early diabetes in PanC, albeit not as an early manifestation of cancer. MiR-20b-5p as more informative marker than CA 19-9 in distinguishing non-PanC with recent diabetes from HS was also uncovered.
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Affiliation(s)
- Francesca Tavano
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Andrea Fontana
- Unit of Biostatistics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Domenica Gioffreda
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Tommaso Biagini
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Orazio Palumbo
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Massimo Carella
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
| | - Angelo Andriulli
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy
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Ozcan-Sınır G, Inan S, Suna S, Tamer CE, Akgül MB, Bagdas D, Sonmez G, Evrensel T, Kaya E, Sarandol E, Dündar HZ, Tarım OF, Ercan I, Sıgırlı D, Incedayı B, Copur OU. Effect of High Fructose Corn Sirup on Pancreatic Ductal Adenocarcinoma Induced by Dimethyl Benzantracene (DMBA) in Rats. Nutr Cancer 2020; 73:339-349. [PMID: 32475178 DOI: 10.1080/01635581.2020.1770811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Increased risk of pancreatic cancer may be associated with consumption of sugar containing foods. The aim of this study was to evaluate the effect of peach nectar containing high fructose corn sirup (HFCS) consumption in a pancreatic carcinogenesis rat model induced by 7,12-Dimethyl benzanthracene (DMBA). Fifty-day-old male Sprague Dawley rats were fed with peach nectar containing HFCS + chow, peach nectar containing sucrose + chow and only chow. After 8 mo, feeding period, each group was divided into two subgroups, in which the rats were implanted with DMBA and no DMBA (sham). Histologic specimens were evaluated according to the routine tissue processing protocol. The animals with ad libitum access to pn-HFCS, pn-sucrose and chow (only) showed significant differences in chow consumption and glucose level. Necropsy and histopathologic findings showed tumor formation in the entire group treated with DMBA. Excluding one rat in chow group, which was classified as poorly differentiated type, the others were classified as moderately differentiated pancreatic ductal adenocarcinoma (PDAC). This study demonstrated that daily intake of HFCS did not increase body weight and there was no effect of peach nectar consumption on the development of PDAC induced by DMBA in rats.
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Affiliation(s)
- Gulsah Ozcan-Sınır
- Department of Food Engineering, Faculty of Agriculture, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Sevda Inan
- Department of Pathology, Faculty of Veterinary Medicine, Tekirdag Namik Kemal University, Tekirdag, Turkey
| | - Senem Suna
- Department of Food Engineering, Faculty of Agriculture, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Canan Ece Tamer
- Department of Food Engineering, Faculty of Agriculture, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Mustafa Barış Akgül
- Department of Surgery, Faculty of Veterinary Medicine, Siirt University, Siirt, Turkey
| | - Deniz Bagdas
- Department of Psychiatry, Yale University School of Medicine, New Heaven, CT, USA
| | - Gursel Sonmez
- Department of Pathology, Faculty of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| | - Turkkan Evrensel
- Department of Medical Oncology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey Görükle
| | - Ekrem Kaya
- Department of Surgery, Faculty of Medicine, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Emre Sarandol
- Department of Biochemistry, Faculty of Medicine, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Halit Ziya Dündar
- Department of Surgery, Faculty of Medicine, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Omer Faruk Tarım
- Department of Paediatric Endocrinology, Faculty of Medicine, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Ilker Ercan
- Department of Biostatistic, Faculty of Medicine, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Deniz Sıgırlı
- Department of Biostatistic, Faculty of Medicine, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Bige Incedayı
- Department of Food Engineering, Faculty of Agriculture, Bursa Uludag University, Görükle, Bursa, Turkey
| | - Omer Utku Copur
- Department of Food Engineering, Faculty of Agriculture, Bursa Uludag University, Görükle, Bursa, Turkey
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Abstract
PURPOSE OF REVIEW The aim was to review evidence about diabetes secondary to hereditary pancreatitis, seeking novel diagnostic and treatment features. RECENT FINDINGS Hereditary pancreatitis (HP) is an autosomal dominant condition, characterized by recurrent episodes of acute pancreatitis, progression to fibrosis, and chronic pancreatitis. Clinical presentation includes diabetes of the exocrine pancreas (DEP). HP prevalence ranges from 0.3 to 0.57 per 100,000 people, with up to 80% of these develop DEP. This condition often requires specific interventions: with regard to metabolic control, metformin is the first choice for those with mild DEP, and for those in advanced disease, insulin is considered the first-line therapy. Insulin analogues and insulin pump therapy are preferred due to the brittle glycemic pattern and risk of hypoglycemia. In case of exocrine insufficiency, pancreatic enzyme replacement therapy is recommended. Pancreatic polypeptide administration is a promising novel treatment feature. DEP due to HP appears to be a misdiagnosed condition. The requirement of specific management demonstrates the importance of this matter; therefore, appropriate recognition and classification are important.
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Affiliation(s)
- Gabriel Xavier Ramalho
- School of Medicine, Faculty of Education and Health Sciences, University Center of Brasilia (UniCEUB), Brasilia, Brazil
| | - Marcio Garrison Dytz
- School of Medicine, Faculty of Education and Health Sciences, University Center of Brasilia (UniCEUB), Brasilia, Brazil.
- Endocrinology Division, Department of Intern Medicine, Sobradinho Regional Hospital, Brasilia, Brazil.
- Endocrinology and Metabolism Medical Residency, Superior School of Health Sciences (ESCS), Brasilia, Brazil.
- Institute of Diabetes and Endocrinology of Brasilia, SHS Qd. 6 Cj. A Bl. E Sl 1119, Brasilia, DF, 70316-902, Brazil.
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Affiliation(s)
- Murray Korc
- From the Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
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40
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Abstract
PURPOSE OF REVIEW A strong association between diabetes mellitus and carcinogenesis has been reported in different organs. The purpose of this review is to summarize the new evidences in relation to diabetes mellitus and its association with the development, prognosis, and therapeutic strategies of head and neck squamous cell carcinomas (HNSCC). RECENT FINDINGS Recent publications suggest that glycemic metabolism is altered in HNSCC. Elevated blood glucose levels, before or around the time of diagnosis, have been reported to reduce survival rates in HNSCC. Also, the homeostasis model assessment-insulin resistance has been independently associated with disease-free survival, suggesting that improving the glycemic control may improve the prognosis in this group of patients.Epidemiological studies revealed that cancer patients with diabetes mellitus have less cancer-related mortality after antiglycemic treatment, opening the option to include antiglycolytic agents, such as metformin, in the therapeutic plan. This finding is in accordance with in-vitro studies that demonstrated a decrease in tumor-cell proliferation with antidiabetic medications. SUMMARY Recent findings highlight the importance of glucose metabolism in the pathogenesis and progression of cancer cells. The knowledge of these altered pathways gives us an opportunity to design target treatments aimed to modulate glucose catabolism.
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Goldberg R, Meirovitz A, Abecassis A, Hermano E, Rubinstein AM, Nahmias D, Grinshpun A, Peretz T, Elkin M. Regulation of Heparanase in Diabetes-Associated Pancreatic Carcinoma. Front Oncol 2019; 9:1405. [PMID: 31921662 PMCID: PMC6914686 DOI: 10.3389/fonc.2019.01405] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/27/2019] [Indexed: 12/18/2022] Open
Abstract
While at least six types of cancer have been associated with diabetes, pancreatic ductal adenocarcinoma (PDAC) and diabetes exhibit a unique bidirectional relationship. Recent reports indicate that majority of PDAC patients display hyperglycemia, and ~50% have concurrent diabetes. In turn, hyperglycemic/diabetic state in PDAC patients fosters enhanced growth and dissemination of the tumor. Heparanase enzyme (the sole mammalian endoglycosidase degrading glycosaminoglycan heparan sulfate) is tightly implicated in PDAC progression, aggressiveness, and therapy resistance. Overexpression of heparanase is a characteristic feature of PDAC, correlating with poor prognosis. However, given the lack of heparanase expression in normal pancreatic tissue, the regulatory mechanisms responsible for induction of the enzyme in PDAC have remained largely unknown. Previously reported inducibility of heparanase gene by diabetic milieu components in several non-cancerous cell types prompted us to hypothesize that in the setting of diabetes-associated PDAC, hyperglycemic state may induce heparanase overexpression. Here, utilizing a mouse model of diet-induced metabolic syndrome/diabetes, we found accelerated PDAC progression in hyperglycemic mice, occurring along with induction of heparanase in PDAC. In vitro, we demonstrated that advanced glycation end-products (AGE), which are largely thought as oxidative derivatives resulting from chronic hyperglycemia, and the receptor for AGE (RAGE) are responsible for heparanase induction in PDAC cells. These findings underscore the new mechanism underlying preferential expression of heparanase in pancreatic cancer. Moreover, taken together with the well-established causal role of the enzyme in PDAC progression, our findings indicate that heparanase may sustain (at least in part) reciprocal causality between diabetes and pancreatic tumorigenesis.
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Affiliation(s)
- Rachel Goldberg
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Amichay Meirovitz
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Alexia Abecassis
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Esther Hermano
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ariel M Rubinstein
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Daniela Nahmias
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Albert Grinshpun
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Tamar Peretz
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Michael Elkin
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Lee M, Sun J, Han M, Cho Y, Lee JY, Nam CM, Kang ES. Nationwide Trends in Pancreatitis and Pancreatic Cancer Risk Among Patients With Newly Diagnosed Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors. Diabetes Care 2019; 42:2057-2064. [PMID: 31431452 DOI: 10.2337/dc18-2195] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 07/29/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Dipeptidyl peptidase 4 inhibitors (DPP-4i) are useful incretin-based antidiabetes drugs. However, there is a concern that DPP-4i may adversely impact the exocrine pancreas, owing to their pleiotropic effects. In this study, we investigated whether DPP-4i are associated with pancreatitis and pancreatic cancer using a nationwide population-based cohort study. RESEARCH DESIGN AND METHODS We included patients newly diagnosed with type 2 diabetes who were treated with antidiabetes drugs (n = 33,208) from 2007 to 2013. The data were obtained from the Korean National Health Insurance Service-Health Screening Cohort database (n = 514,866). Risk was estimated using a Cox proportional hazards model with time-dependent covariates. A 6-month lag time was used to account for a possible latency time. The risk across various time segments since the first prescription of DPP-4i was also analyzed. RESULTS Out of 33,208 subjects, 10,218 were new users of DPP-4i and 22,990 were new users of other antidiabetes drugs. DPP-4i significantly increased the risks of pancreatitis (adjusted hazard ratio [aHR] 1.24, 95% CI 1.01-1.52; P = 0.037) and pancreatic cancer (aHR 1.81, 95% CI 1.16-2.82; P = 0.009) with a 6-month drug use lag period. The risk of pancreatitis and pancreatic cancer was generally consistent in the first 12 months and 1 year after the initial prescription without showing an increasing trend according to exposure duration. CONCLUSIONS DPP-4i use is associated with increased risks of pancreatitis and pancreatic cancer in patients with newly diagnosed type 2 diabetes. However, the absence of increasing trend according to exposure duration suggests the chances of reverse causality, and long-term pancreatic safety of DPP-4i has to be further investigated.
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Affiliation(s)
- Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jiyu Sun
- Biostatistics and Computing, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Minkyung Han
- Department of Public Health, Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yongin Cho
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ji-Yeon Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chung Mo Nam
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea .,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
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Li Y, Bian X, Wei S, He M, Yang Y. The relationship between pancreatic cancer and type 2 diabetes: cause and consequence. Cancer Manag Res 2019; 11:8257-8268. [PMID: 31571983 PMCID: PMC6750859 DOI: 10.2147/cmar.s211972] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 08/23/2019] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is a devastating and lethal malignant disease and it is well known that there is a complex bidirectional relationship between PC and type 2 diabetes mellitus (T2DM). In order to more deeply summarize the relationship between them, this article summarizes the epidemiological data on the relationship between PC and T2DM in the past 5 years, and further explains the mechanism of interaction between them. Meanwhile, it also summed up the effects of drug therapy for T2DM on PC and the impact of T2DM on surgical resection of PC. Epidemiological studies clearly indicate that the risk of PC is increased in patients with T2DM. But increasing epidemiological data points out that PC also acts as a cause of T2DM and new-onset T2DM is sign and consequence of PC. Insulin resistance, hyperinsulinemia, hyperglycemia, and chronic inflammation are the mechanisms of T2DM-Associated PC. Metformin decreases the risk of PC, while insulin therapy increases the risk of PC. Besides, studies have shown that T2DM decreases the survival in patients with PC resection.
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Affiliation(s)
- Yan Li
- Department of Gerontology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Xiaohui Bian
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Shuyi Wei
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Meizhi He
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Yuelian Yang
- Department of Gerontology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
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Frola C, Somasundaram M, Hariharan D, Kolaityte V, Mohandas S, Stättner S, Yip VS. The role of surgery in chronic pancreatitis. Eur Surg 2019. [DOI: 10.1007/s10353-019-0591-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Hart PA, Andersen DK, Mather KJ, Castonguay AC, Bajaj M, Bellin MD, Bradley D, Contreras N, Habtezion A, Korc M, Kudva Y, Petrov MS, Whitcomb DC, Yadav D, Yuan Y, Rinaudo JA, Srivastava S, Serrano J, on behalf of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC). Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: Rationale and Methodology for the DETECT Study From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas 2019; 47:1239-1243. [PMID: 30325863 PMCID: PMC6195331 DOI: 10.1097/mpa.0000000000001168] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pancreatogenic diabetes mellitus is most commonly the result of chronic pancreatitis but can also occur secondary to pancreatic cancer. The early identification of pancreatogenic diabetes and distinction from the more prevalent type 2 diabetes are clinically significant; however, currently, there is no validated method to differentiate these diabetes subtypes. We describe a study, "Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: the DETECT study," that seeks to address this knowledge gap. The DETECT study is a multicenter study that will examine differences in hormone and glucose excursions after a mixed meal test. The study will also create a biorepository that will be used to evaluate novel diagnostic biomarkers for differentiating these diabetes subtypes.
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Affiliation(s)
- Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Kieren J. Mather
- Division of Endocrinology & Metabolism, Indiana University School of Medicine, Indianapolis IN
| | - Alicia C. Castonguay
- Department of Neurology, University of Toledo, College of Medicine, Toledo, OH
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mandeep Bajaj
- Section of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
| | - Melena D. Bellin
- Departments of Pediatrics and Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - David Bradley
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Noemy Contreras
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Murray Korc
- Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine, the Melvin and Bren Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indianapolis, IN
| | - Yogish Kudva
- Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN
| | - Maxim S. Petrov
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - David C. Whitcomb
- Departments of Medicine, Cell Biology & Molecular Physiology, and Department of Human Genetics, University of Pittsburgh, and UPMC, Pittsburgh, PA
| | - Dhiraj Yadav
- Division of Gastroenterology & Hepatology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Ying Yuan
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jo Ann Rinaudo
- Cancer Biomarker Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Sudhir Srivastava
- Cancer Biomarker Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Jose Serrano
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
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Wang G, Yin L, Peng Y, Gao Y, Gao H, Zhang J, Lv N, Miao Y, Lu Z. Insulin promotes invasion and migration of KRAS G12D mutant HPNE cells by upregulating MMP-2 gelatinolytic activity via ERK- and PI3K-dependent signalling. Cell Prolif 2019; 52:e12575. [PMID: 30838710 PMCID: PMC6536446 DOI: 10.1111/cpr.12575] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 12/16/2018] [Accepted: 12/18/2018] [Indexed: 12/11/2022] Open
Abstract
Objectives Hyperinsulinemia is a risk factor for pancreatic cancer, but the function of insulin in carcinogenesis is unclear, so this study aimed to elucidate the carcinogenic effects of insulin and the synergistic effect with the KRAS mutation in the early stage of pancreatic cancer. Materials and methods A pair of immortalized human pancreatic duct‐derived cells, hTERT‐HPNE E6/E7/st (HPNE) and its oncogenic KRASG12D variant, hTERT‐HPNE E6/E7/KRASG12D/st (HPNE‐mut‐KRAS), were used to investigate the effect of insulin. Cell proliferation, migration and invasion were assessed using Cell Counting Kit‐8 and transwell assays, respectively. The expression of E‐cadherin, N‐cadherin, vimentin and matrix metalloproteinases (MMP‐2, MMP‐7 and MMP‐9) was evaluated by Western blotting and/or qRT‐PCR. The gelatinase activity of MMP‐2 and MMP‐9 in conditioned media was detected using gelatin zymography. The phosphorylation status of AKT, GSK3β, p38, JNK and ERK1/2 MAPK was determined by Western blotting. Results The migration and invasion ability of HPNE cells was increased after the introduction of the mutated KRAS gene, together with an increased expression of MMP‐2. These effects were further enhanced by the simultaneous administration of insulin. The use of MMP‐2 siRNA confirmed that MMP‐2 was involved in the regulation of cell invasion. Furthermore, there was a concentration‐ and time‐dependent increase in gelatinase activity after insulin treatment, which could be reversed by an insulin receptor tyrosine kinase inhibitor (HNMPA‐(AM)3). In addition, insulin markedly enhanced the phosphorylation of PI3K/AKT, p38, JNK and ERK1/2 MAPK pathways, with wortmannin or LY294002 (a PI3K‐specific inhibitor) and PD98059 (a MEK1‐specific inhibitor) significantly inhibiting the insulin‐induced increase in MMP‐2 gelatinolytic activity. Conclusions Taken together, these results suggest that insulin induced migration and invasion in HPNE and HPNE‐mut‐KRAS through PI3K/AKT and ERK1/2 activation, with MMP‐2 gelatinolytic activity playing a vital role in this process. These findings may provide a new therapeutic target for preventing carcinogenesis and the evolution of pancreatic cancer with a background of hyperinsulinemia.
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Affiliation(s)
- Guangfu Wang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Lingdi Yin
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yunpeng Peng
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yong Gao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Hao Gao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Jingjing Zhang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Nan Lv
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Zipeng Lu
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
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Abstract
Chronic pancreatitis (CP) may remain undiagnosed for years until patients exhibit manifestations, such as pain and exocrine or endocrine insufficiency. Some patients with CP develop serious complications, such as malignancy or peripancreatic fluid collections. Considering CP in at-risk patients such as those with a long-standing history of alcohol or tobacco use is key to establishing the diagnosis. Management involves reducing and eliminating exposures, dietary modification, treatment of pancreatic insufficiency, assessing for complications, and surveillance for neoplasia. The management of CP is often multidisciplinary involving medical, endoscopic, and surgical options for therapy.
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Affiliation(s)
- Vaishali Patel
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, 1365 Clifton Road, Northeast, Building B, Suite 1200, Atlanta, GA 30322, USA
| | - Field Willingham
- Division of Digestive Diseases, Department of Medicine, Emory University Hospital, Children's Healthcare of Atlanta, Emory University School of Medicine, 1365 Clifton Road, Northeast, Building B, Suite 1200, Atlanta, GA 30322, USA.
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48
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Diaz KE, Lucas AL. Familial Pancreatic Ductal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:36-43. [PMID: 30558720 PMCID: PMC7073774 DOI: 10.1016/j.ajpath.2018.06.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 05/21/2018] [Accepted: 06/11/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), although a rare disease, has a poor prognosis. With 5-year overall survival of 8%, there is a critical need to detect PDAC early or at a premalignant stage. Current screening methods are largely imaging based, but a more focused screening approach based on modifiable and nonmodifiable risk factors may improve the efficacy and likely outcomes of screening. In addition, the pathologic mechanisms that lead to the development of PDAC are discussed in an effort to further understand the targets of pancreatic cancer screening. The focus of this article will be inherited pancreatic cancer syndromes and familial pancreatic cancer, which together compose up to 10% of PDAC. Understanding the methods and targets of PDAC screening in high-risk individuals may translate to improved morbidity and mortality.
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Affiliation(s)
- Kelly E Diaz
- Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Aimee L Lucas
- Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
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Bhattamisra SK, Siang TC, Rong CY, Annan NC, Sean EHY, Xi LW, Lyn OS, Shan LH, Choudhury H, Pandey M, Gorain B. Type-3c Diabetes Mellitus, Diabetes of Exocrine Pancreas - An Update. Curr Diabetes Rev 2019; 15:382-394. [PMID: 30648511 DOI: 10.2174/1573399815666190115145702] [Citation(s) in RCA: 29] [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: 06/07/2018] [Revised: 11/02/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The incidence of diabetes is increasing steeply; the number of diabetics has doubled over the past three decades. Surprisingly, the knowledge of type 3c diabetes mellitus (T3cDM) is still unclear to the researchers, scientist and medical practitioners, leading towards erroneous diagnosis, which is sometimes misdiagnosed as type 1 diabetes mellitus (T1DM), or more frequently type 2 diabetes mellitus (T2DM). This review is aimed to outline recent information on the etiology, pathophysiology, diagnostic procedures, and therapeutic management of T3cDM patients. METHODS The literature related to T3cDM was thoroughly searched from the public domains and reviewed extensively to construct this article. Further, existing literature related to the other forms of diabetes is reviewed for projecting the differences among the different forms of diabetes. Detailed and updated information related to epidemiological evidence, risk factors, symptoms, diagnosis, pathogenesis and management is structured in this review. RESULTS T3cDM is often misdiagnosed as T2DM due to the insufficient knowledge differentiating between T2DM and T3cDM. The pathogenesis of T3cDM is explained which is often linked to the history of chronic pancreatitis, pancreatic cancer. Inflammation, and fibrosis in pancreatic tissue lead to damage both endocrine and exocrine functions, thus leading to insulin/glucagon insufficiency and pancreatic enzyme deficiency. CONCLUSION Future advancements should be accompanied by the establishment of a quick diagnostic tool through the understanding of potential biomarkers of the disease and newer treatments for better control of the diseased condition.
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Affiliation(s)
- Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Tiew Chin Siang
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Chieng Yi Rong
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Naveenya Chetty Annan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Esther Ho Yung Sean
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Lim Wen Xi
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ong Siu Lyn
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Liew Hui Shan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Bapi Gorain
- School of Pharmacy, Taylor's University, 1, Jalan Taylors, 47500 Subang Jaya, Selangor, Malaysia
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Luo G, Liu N. An integrative theory for cancer (Review). Int J Mol Med 2018; 43:647-656. [PMID: 30483756 PMCID: PMC6317675 DOI: 10.3892/ijmm.2018.4004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022] Open
Abstract
In the integrative theory, chronic irritations induce tumors with genetic alterations and rapid proliferative ability. Tumor cells reprogram the metabolism and employ aerobic glycolysis to sustain rapid growth. The host provides both the nutrients and exhaust system to support tumor growth via the tumor microenvironment. Under certain conditions, such as aging, diabetes, obesity and a high‑fat diet, the exhaust system is impaired, triggering a metabolic imbalance between the tumor and host. This is similar to a problematic car with an advanced motor with an out‑of‑date exhaust system. The metabolic imbalance causes a metabolic catastrophe, making tumor cells reside in a dismal environment and forcing them to invade, metastasize and undergo necrosis. Tumor necrosis, particularly in metastases, leads to non‑specific systemic inflammation, which is the major cause of cancer‑related mortality. On the whole, the integrative theory views cancer in an integrative manner and proposes that both genetic alterations and tumor‑host interaction as regards metabolism and immunology determine the destiny of the tumor and host. Although cancer is a genetic disease, tumor biology is basically the nature of the host.
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Affiliation(s)
- Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Na Liu
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, P.R. China
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