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Saha S, Ghosh S, Ghosh S, Nandi S, Nayak A. Unraveling the complexities of colorectal cancer and its promising therapies - An updated review. Int Immunopharmacol 2024; 143:113325. [PMID: 39405944 DOI: 10.1016/j.intimp.2024.113325] [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: 05/04/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 10/30/2024]
Abstract
Colorectal cancer (CRC) continues to be a global health concern, necessitating further research into its complex biology and innovative treatment approaches. The etiology, pathogenesis, diagnosis, and treatment of colorectal cancer are summarized in this thorough review along with recent developments. The multifactorial nature of colorectal cancer is examined, including genetic predispositions, environmental factors, and lifestyle decisions. The focus is on deciphering the complex interactions between signaling pathways such as Wnt/β-catenin, MAPK, TGF-β as well as PI3K/AKT that participate in the onset, growth, and metastasis of CRC. There is a discussion of various diagnostic modalities that span from traditional colonoscopy to sophisticated molecular techniques like liquid biopsy and radiomics, emphasizing their functions in early identification, prognostication, and treatment stratification. The potential of artificial intelligence as well as machine learning algorithms in improving accuracy as well as efficiency in colorectal cancer diagnosis and management is also explored. Regarding therapy, the review provides a thorough overview of well-known treatments like radiation, chemotherapy, and surgery as well as delves into the newly-emerging areas of targeted therapies as well as immunotherapies. Immune checkpoint inhibitors as well as other molecularly targeted treatments, such as anti-epidermal growth factor receptor (anti-EGFR) as well as anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies, show promise in improving the prognosis of colorectal cancer patients, in particular, those suffering from metastatic disease. This review focuses on giving readers a thorough understanding of colorectal cancer by considering its complexities, the present status of treatment, and potential future paths for therapeutic interventions. Through unraveling the intricate web of this disease, we can develop a more tailored and effective approach to treating CRC.
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Affiliation(s)
- Sayan Saha
- Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Rd, Sahid Colony, Panihati, Kolkata, West Bengal 700114, India
| | - Shreya Ghosh
- Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Rd, Sahid Colony, Panihati, Kolkata, West Bengal 700114, India
| | - Suman Ghosh
- Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Rd, Sahid Colony, Panihati, Kolkata, West Bengal 700114, India
| | - Sumit Nandi
- Department of Pharmacology, Gupta College of Technological Sciences, Asansol, West Bengal 713301, India
| | - Aditi Nayak
- Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Rd, Sahid Colony, Panihati, Kolkata, West Bengal 700114, India.
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Calabrese C, Miserocchi G, De Vita A, Spadazzi C, Cocchi C, Vanni S, Gabellone S, Martinelli G, Ranallo N, Bongiovanni A, Liverani C. Lipids and adipocytes involvement in tumor progression with a focus on obesity and diet. Obes Rev 2024; 25:e13833. [PMID: 39289899 DOI: 10.1111/obr.13833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 08/26/2024] [Accepted: 08/29/2024] [Indexed: 09/19/2024]
Abstract
The adipose tissue is a complex organ that can play endocrine, metabolic, and immune regulatory roles in cancer. In particular, adipocytes provide metabolic substrates for cancer cell proliferation and produce signaling molecules that can stimulate cell adhesion, migration, invasion, angiogenesis, and inflammation. Cancer cells, in turn, can reprogram adipocytes towards a more inflammatory state, resulting in a vicious cycle that fuels tumor growth and evolution. These mechanisms are enhanced in obesity, which is associated with the risk of developing certain tumors. Diet, an exogenous source of lipids with pro- or anti-inflammatory functions, has also been connected to cancer risk. This review analyzes how adipocytes and lipids are involved in tumor development and progression, focusing on the relationship between obesity and cancer. In addition, we discuss how diets with varying lipid intakes can affect the disease outcomes. Finally, we introduce novel metabolism-targeted treatments and adipocyte-based therapies in oncology.
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Affiliation(s)
- Chiara Calabrese
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giacomo Miserocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Alessandro De Vita
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Spadazzi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Claudia Cocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Silvia Vanni
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Sofia Gabellone
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Giovanni Martinelli
- Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Nicoletta Ranallo
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Alberto Bongiovanni
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Chiara Liverani
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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Jiménez-Cortegana C, Gutiérrez-García C, Sánchez-Jiménez F, Vilariño-García T, Flores-Campos R, Pérez-Pérez A, Garnacho C, Sánchez-León ML, García-Domínguez DJ, Hontecillas-Prieto L, Palazón-Carrión N, De La Cruz-Merino L, Sánchez-Margalet V. Impact of obesity‑associated myeloid‑derived suppressor cells on cancer risk and progression (Review). Int J Oncol 2024; 65:79. [PMID: 38940351 PMCID: PMC11251741 DOI: 10.3892/ijo.2024.5667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 06/12/2024] [Indexed: 06/29/2024] Open
Abstract
Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low‑grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid‑derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesity‑associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity‑associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSC‑driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity‑related cancer.
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Affiliation(s)
- Carlos Jiménez-Cortegana
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Cristian Gutiérrez-García
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Flora Sánchez-Jiménez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Teresa Vilariño-García
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Rocio Flores-Campos
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Carmen Garnacho
- Department of Normal and Pathological Histology and Cytology, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Maria L. Sánchez-León
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Daniel J. García-Domínguez
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Lourdes Hontecillas-Prieto
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
| | - Natalia Palazón-Carrión
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Luis De La Cruz-Merino
- Oncology Service, Virgen Macarena University Hospital, School of Medicine, University of Seville, 41009 Seville, Spain
- Institute of Biomedicine of Seville, Virgen Macarena University Hospital, CSIC, University of Seville, Seville 41013, Spain
| | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain
- Institute of Biomedicine of Seville, Virgen Macarena University Hospital, CSIC, University of Seville, Seville 41013, Spain
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Poltronieri TS, Pérsico RS, Viana LV. Body adipose tissue depots and treatment outcomes for women with breast cancer: A systematic review. Clin Nutr 2024; 43:1033-1042. [PMID: 38547637 DOI: 10.1016/j.clnu.2024.03.010] [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: 03/30/2023] [Revised: 02/14/2024] [Accepted: 03/16/2024] [Indexed: 05/04/2024]
Abstract
BACKGROUND & AIMS Excessive adipose tissue is associated with poorer prognosis in women with breast cancer (BC). However, several body adiposity depots, such as visceral (VAT), subcutaneous (SAT), intermuscular (IMAT), and gluteofemoral adipose tissues (GFAT) may have heterogeneous metabolic roles and health effects in these patients. This systematic review aims to evaluate the impact of different body adipose tissue depots, assessed via computed tomography (CT), on treatment outcomes for women with BC. We hypothesize that distinct body adipose tissue depots may be associated differently with outcomes in patients with BC. METHODS A comprehensive bibliographical search was conducted using PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases (until January 2024). The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. RESULTS The final sample comprised 23 retrospective studies (n = 12,462), with fourteen presenting good quality. A lack of standardization in CT body adipose tissue depots measurement and outcome presentation precluded quantitative analysis. Furthermore, most included studies had heterogeneous clinical characteristics. Survival and treatment response were the most prevalent outcomes. VAT (n = 19) and SAT (n = 17) were the most frequently evaluated depots and their increase was associated with worse outcomes, mainly in terms of survival. IMAT (n = 4) presented contradictory findings and a higher GFAT (n = 1) was associated with better outcomes. CONCLUSION This systematic review found an association between increased VAT and SAT with worse outcomes in patients with BC. However, due to the heterogeneity of the included studies, further research with homogeneous methodologies is necessary to better understand the impact of body adipose tissue depots on treatment outcomes. Such knowledge could lead to improved care for this patient population.
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Affiliation(s)
- Taiara Scopel Poltronieri
- Programa de Pós-Graduação em Ciências Médicas, Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
| | - Raquel Stocker Pérsico
- Programa de Pós-Graduação em Ciências Médicas, Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
| | - Luciana Verçoza Viana
- Programa de Pós-Graduação em Ciências Médicas, Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
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Alimperti A, Alikari V, Tsironi M, Rojas Gil AP, Papageorgiou D, Kolovos P, Panagiotou A, Panoutsopoulos GI, Lavdaniti M, Zyga S. Lipid Disturbances in Breast Cancer Patients during Chemotherapy. NURSING REPORTS 2023; 13:1500-1510. [PMID: 37987405 PMCID: PMC10661266 DOI: 10.3390/nursrep13040126] [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: 09/09/2023] [Revised: 10/17/2023] [Accepted: 10/24/2023] [Indexed: 11/22/2023] Open
Abstract
Breast cancer is the most common cancer in women. Cardiovascular diseases are common complications after chemotherapy due to the effect of the drug on lipid levels. This study aimed to explore the changes in lipid profiles in patients with breast cancer under chemotherapy. METHODS In this prospective study, 50 patients with breast cancer participated. Three biochemical-lipid hematological tests were performed: total cholesterol (TC), triglycerides (TGs), High-Density Lipoprotein (HDL-C), and Low-Density Lipoprotein (LDL-C) before initiation (pre-chemotherapy), at the start (first follow-up), and at the completion (second follow-up) of the first cycle of chemotherapy. Statistical significance was set at p < 0.05. Analyses were conducted using SPSS Statistical Software (version 22.0). RESULTS Mean TC values increased significantly at second follow-up. TGs values decreased significantly from first to second follow-up. HDL-C was significantly lower at first follow-up compared with pre-chemotherapy and was similar to the pre-chemotherapy levels at second follow-up. LDL-C values were significantly higher at second follow-up compared with pre-chemotherapy measurement. Significantly positive correlations of BMI with pre-chemotherapy LDL-C, first follow-up TC, first follow-up LDL-C, second follow-up TC, and second follow-up LDL-C were found. CONCLUSIONS There is a statistically significant increase in the levels of TC and LDL-C in breast cancer patients during chemotherapy. This study was not registered.
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Affiliation(s)
- Aikaterini Alimperti
- Department of Nursing, University of Peloponnese, 22131 Tripolis, Greece; (A.A.); (M.T.); (A.P.R.G.); (D.P.); (P.K.); (A.P.); (S.Z.)
| | - Victoria Alikari
- Department of Nursing, University of West Attica, 12243 Egaleo, Greece
| | - Maria Tsironi
- Department of Nursing, University of Peloponnese, 22131 Tripolis, Greece; (A.A.); (M.T.); (A.P.R.G.); (D.P.); (P.K.); (A.P.); (S.Z.)
| | - Andrea Paola Rojas Gil
- Department of Nursing, University of Peloponnese, 22131 Tripolis, Greece; (A.A.); (M.T.); (A.P.R.G.); (D.P.); (P.K.); (A.P.); (S.Z.)
| | - Dimitrios Papageorgiou
- Department of Nursing, University of Peloponnese, 22131 Tripolis, Greece; (A.A.); (M.T.); (A.P.R.G.); (D.P.); (P.K.); (A.P.); (S.Z.)
| | - Petros Kolovos
- Department of Nursing, University of Peloponnese, 22131 Tripolis, Greece; (A.A.); (M.T.); (A.P.R.G.); (D.P.); (P.K.); (A.P.); (S.Z.)
| | - Aspasia Panagiotou
- Department of Nursing, University of Peloponnese, 22131 Tripolis, Greece; (A.A.); (M.T.); (A.P.R.G.); (D.P.); (P.K.); (A.P.); (S.Z.)
| | - George I. Panoutsopoulos
- Department of Nutrition Science and Dietetics, University of Peloponnese, 22131 Tripolis, Greece;
| | - Maria Lavdaniti
- Department of Nursing, International Hellenic University, 57001 Nea Moudania, Greece;
| | - Sofia Zyga
- Department of Nursing, University of Peloponnese, 22131 Tripolis, Greece; (A.A.); (M.T.); (A.P.R.G.); (D.P.); (P.K.); (A.P.); (S.Z.)
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Tzschaschel M, Friedl TWP, Schochter F, Schütze S, Polasik A, Fehm T, Pantel K, Schindlbeck C, Schneeweiss A, Schreier J, Tesch H, Lorenz R, Aivazova-Fuchs V, Häberle L, Fasching P, Janni W, Rack BK, Fink V. Association Between Obesity and Circulating Tumor Cells in Early Breast Cancer Patients. Clin Breast Cancer 2023:S1526-8209(23)00132-5. [PMID: 37336651 DOI: 10.1016/j.clbc.2023.05.011] [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: 04/05/2023] [Revised: 05/17/2023] [Accepted: 05/21/2023] [Indexed: 06/21/2023]
Abstract
BACKGROUND Obesity and the presence of circulating tumor cells (CTCs) before and/or after chemotherapy are associated with poor outcome in breast cancer (BC) patients. The activation of oncogenic pathways in fatty tissue leads to cell proliferation, suggesting a possible link between obesity and CTCs. MATERIALS AND METHODS In the phase III SUCCESS A trial, 3754 patients with early BC were randomized to 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine. Data of 1088 patients with CTC assessments (CellSearch-System; Menarini Silicon Biosystems, Italy) and body mass index (BMI) measurements both before and after chemotherapy were available. Patients were classified according to the WHO's international definitions as underweight, normal weight, overweight, or obese, and according to their weight-change during chemotherapy into a weight-loss group (> 5% decrease), stable-weight group (≤ 5% weight-change) or weight-gain group (>5% increase). Associations between CTC positivity and, BMI or weight-change group were analyzed using frequency-table methods. RESULTS At study entry, 47.4% patients were underweight or normal weight, 33.6% were overweight and 18.9% were obese. Before and after chemotherapy, CTCs were detected in 20.1% and 22.6% of patients, respectively. There was no association between CTC positivity and BMI before (P = 0.104) or after (P = 0.051) chemotherapy. Furthermore, there was no association between weight-change group and CTC status before/after chemotherapy (P = 0.332). CONCLUSIONS According to our analysis, the risk factors obesity and prevalence of CTCs are not associated and may represent independent prognostic factors.
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Affiliation(s)
- Marie Tzschaschel
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
| | - Thomas W P Friedl
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Fabienne Schochter
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Sabine Schütze
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Arkadius Polasik
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Tanja Fehm
- Department of Gynecology and Obstetrics, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Hans Tesch
- Onkologische Gemeinschaftspraxis, Frankfurt, Germany
| | - Ralf Lorenz
- Gemeinschaftspraxis Dr. Lorenz, Hecker und Wesche, Braunschweig, Germany
| | | | - Lothar Häberle
- Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, ComprehensiveCancer Center Erlangen-Nuremberg, Erlangen, Germany
| | - Peter Fasching
- Department of Obstetrics and Gynecology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, ComprehensiveCancer Center Erlangen-Nuremberg, Erlangen, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Brigitte Kathrin Rack
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany; Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany
| | - Visnja Fink
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
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Bevel MS, Tsai MH, Parham A, Andrzejak SE, Jones S, Moore JX. Association of Food Deserts and Food Swamps With Obesity-Related Cancer Mortality in the US. JAMA Oncol 2023:2804691. [PMID: 37140933 PMCID: PMC10160992 DOI: 10.1001/jamaoncol.2023.0634] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Importance Obesity-related cancers account for 40% of all cancers in the US. Healthy food consumption is a modifiable factor shown to reduce obesity-related cancer mortality, but residing in areas with less access to grocery stores (food deserts) or higher access to fast food (food swamps) reduces healthy food access and has been understudied. Objective To analyze the association of food deserts and food swamps with obesity-related cancer mortality in the US. Design, Setting, and Participants This cross-sectional ecologic study used US Department of Agriculture Food Environment Atlas data from 2012, 2014, 2015, 2017, and 2020 and Centers for Disease Control and Prevention mortality data from 2010 to 2020. A total of 3038 US counties or county equivalents with complete information on food environment scores and obesity-related cancer mortality data were included. An age-adjusted, generalized, mixed-effects regression model was performed for the association of food desert and food swamp scores with obesity-related cancer mortality rates. Data were analyzed from September 9, 2022, to September 30, 2022. Exposures Food swamp score was calculated as the ratio of fast-food and convenience stores to grocery stores and farmers markets. Higher food swamp and food desert scores (20.0 to ≥58.0) indicated counties with fewer healthy food resources. Main Outcomes and Measures Obesity-related cancer (based on the International Agency for Research on Cancer evidence between obesity and 13 types of cancer) mortality rates were categorized as high (≥71.8 per 100 000 population) vs low (<71.8 per 100 000 population) per county. Results A total of 3038 counties or county equivalents with high obesity-related cancer mortality rates had a higher percentage of non-Hispanic Black residents (3.26% [IQR, 0.47%-26.35%] vs 1.77% [IQR, 0.43%-8.48%]), higher percentage of persons older than 65 years (15.71% [IQR, 13.73%-18.00%] vs 15.40% [IQR, 12.82%-18.09%]), higher poverty rates (19.00% [IQR, 14.20%-23.70%] vs 14.40% [IQR, 11.00%-18.50%]), higher adult obesity rates (33.00% [IQR, 32.00%-35.00%] vs 32.10% [IQR, 29.30%-33.20%]), and higher adult diabetes rates (12.50% [IQR, 11.00%-14.20%] vs 10.70% [IQR, 9.30%-12.40%]) compared with counties or county equivalents with low obesity-related cancer mortality. There was a 77% increased odds of having high obesity-related cancer mortality rates among US counties or county equivalents with high food swamp scores (adjusted odds ratio, 1.77; 95% CI, 1.43-2.19). A positive dose-response relationship among 3 levels of food desert and food swamp scores and obesity-related cancer mortality was also observed. Conclusions and Relevance The findings of this cross-sectional ecologic study suggest that policy makers, funding agencies, and community stakeholders should implement sustainable approaches to combating obesity and cancer and establishing access to healthier food, such as creating more walkable neighborhoods and community gardens.
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Affiliation(s)
- Malcolm Seth Bevel
- Cancer Prevention, Control and Population Health, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta
| | - Meng-Han Tsai
- Cancer Prevention, Control and Population Health, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta
- Georgia Prevention Institute, Medical College of Georgia, Augusta University, Augusta
| | - April Parham
- Cancer Prevention, Control and Population Health, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta
| | - Sydney Elizabeth Andrzejak
- Cancer Prevention, Control and Population Health, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta
| | - Samantha Jones
- Cancer Prevention, Control and Population Health, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta
- Georgia Prevention Institute, Medical College of Georgia, Augusta University, Augusta
| | - Justin Xavier Moore
- Cancer Prevention, Control and Population Health, Georgia Cancer Center, Department of Medicine, Medical College of Georgia, Augusta University, Augusta
- Institute of Preventive and Public Health, Medical College of Georgia, Augusta University, Augusta
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Xie WJ, Li J. Obesity and cancer stem cells: Roles in cancer initiation, progression and therapy resistance. World J Stem Cells 2023; 15:120-135. [PMID: 37181008 PMCID: PMC10173809 DOI: 10.4252/wjsc.v15.i4.120] [Citation(s) in RCA: 2] [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: 11/28/2022] [Revised: 01/28/2023] [Accepted: 03/17/2023] [Indexed: 04/26/2023] Open
Abstract
Obesity, the global pandemic since industrialization, is the number one lifestyle-related risk factor for premature death, which increases the incidence and mortality of various diseases and conditions, including cancer. In recent years, the theory of cancer stem cells (CSCs), which have the capacity for self-renewal, metastasis and treatment resistance, has been bolstered by increasing evidence. However, research on how obesity affects CSCs to facilitate cancer initiation, progression and therapy resistance is still in its infancy, although evidence has already begun to accumulate. Regarding the ever-increasing burden of obesity and obesity-related cancer, it is pertinent to summarize evidence about the effects of obesity on CSCs, as elucidating these effects will contribute to the improvement in the management of obesity-related cancers. In this review, we discuss the association between obesity and CSCs, with a particular focus on how obesity promotes cancer initiation, progression and therapy resistance through CSCs and the mechanisms underlying these effects. In addition, the prospect of preventing cancer and targeting the mechanisms linking obesity and CSCs to reduce cancer risk or to improve the survival of patients with cancer is considered.
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Affiliation(s)
- Wen-Jie Xie
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China
| | - Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang 621000, Sichuan Province, China
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Makrakis D, Rounis K, Tsigkas AP, Georgiou A, Galanakis N, Tsakonas G, Ekman S, Papadaki C, Monastirioti A, Kontogianni M, Gioulbasanis I, Mavroudis D, Agelaki S. Effect of body tissue composition on the outcome of patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors. PLoS One 2023; 18:e0277708. [PMID: 36763597 PMCID: PMC9916610 DOI: 10.1371/journal.pone.0277708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 11/01/2022] [Indexed: 02/11/2023] Open
Abstract
Obesity and sarcopenia have been reported to affect outcomes in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We analyzed prospective data from 52 patients with non-oncogene driven metastatic NSCLC treated with ICIs. Body tissue composition was calculated by measuring the fat and muscle densities at the level of 3rd lumbar vertebra in each patient computed tomography scan before ICI initiation using sliceOmatic tomovision. We converted the densities to indices [Intramuscular Fat Index (IMFI), Visceral Fat Index (VFI), Subcutaneous Fat Index (SFI), Lumbar Skeletal Muscle Index (LSMI)] by dividing them by height in meters squared. Patients were dichotomized based on their baseline IMFI, VFI and SFI according to their gender-specific median value. The cut-offs that were set for LMSI values were 55 cm2/m2 for males and 39 cm2/m2 for females. SFI distribution was significantly higher (p = 0.040) in responders compared to non-responders. None of the other variables affected response rates. Low LSMI HR: 2.90 (95% CI: 1.261-6.667, p = 0.012) and low SFI: 2.20 (95% CI: 1.114-4.333, p = 0.023) values predicted for inferior OS. VFI and IMFI values did not affect survival. Subcutaneous adipose and skeletal muscle tissue composition significantly affected immunotherapy outcomes in our cohort.
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Affiliation(s)
- Dimitrios Makrakis
- Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece
- Jacobi Medical Center, Albert Einstein College of Medicine, The Bronx, NY, United States of America
| | - Konstantinos Rounis
- Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece
- Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden
| | - Alexandros-Pantelis Tsigkas
- Department of Nutrition & Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
| | - Alexandra Georgiou
- Department of Nutrition & Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
| | - Nikolaos Galanakis
- Department of Medical Imaging, University General Hospital, Heraklion, Crete, Greece
| | - George Tsakonas
- Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Simon Ekman
- Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Chara Papadaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - Alexia Monastirioti
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - Meropi Kontogianni
- Department of Nutrition & Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece
| | - Ioannis Gioulbasanis
- Department of Medical Oncology, Animus Kyanus Stavros General Clinic, Larissa, Greece
| | - Dimitris Mavroudis
- Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - Sofia Agelaki
- Department of Medical Oncology, University General Hospital, Heraklion, Crete, Greece
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
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10
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Thimotheo Batista JP, Santos Marzano LA, Menezes Silva RA, de Sá Rodrigues KE, Simões E Silva AC. Chemotherapy and Anticancer Drugs Adjustment in Obesity: A Narrative Review. Curr Med Chem 2023; 30:1003-1028. [PMID: 35946096 DOI: 10.2174/0929867329666220806140204] [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: 10/18/2021] [Revised: 03/08/2022] [Accepted: 03/31/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Obese individuals have higher rates of cancer incidence and cancer- related mortality. The worse chemotherapy outcomes observed in this subset of patients are multifactorial, including the altered physiology in obesity and its impact on pharmacokinetics, the possible increased risk of underdosing, and treatment-related toxicity. AIMS The present review aimed to discuss recent data on physiology, providing just an overall perspective and pharmacokinetic alterations in obesity concerning chemotherapy. We also reviewed the controversies of dosing adjustment strategies in adult and pediatric patients, mainly addressing the use of actual total body weight and ideal body weight. METHODS This narrative review tried to provide the best evidence to support antineoplastic drug dosing strategies in children, adolescents, and adults. RESULTS Cardiovascular, hepatic, and renal alterations of obesity can affect the distribution, metabolism, and clearance of drugs. Anticancer drugs have a narrow therapeutic range, and variations in dosing may result in either toxicity or underdosing. Obese patients are underrepresented in clinical trials that focus on determining recommendations for chemotherapy dosing and administration in clinical practice. After considering associated comorbidities, the guidelines recommend that chemotherapy should be dosed according to body surface area (BSA) calculated with actual total body weight, not an estimate or ideal weight, especially when the intention of therapy is the cure. CONCLUSION The actual total body weight dosing appears to be a better approach to dosing anticancer drugs in both adults and children when aiming for curative results, showing no difference in toxicity and no limitation in treatment outcomes compared to adjusted doses.
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Affiliation(s)
- João Pedro Thimotheo Batista
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil
| | - Lucas Alexandre Santos Marzano
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil
| | - Renata Aguiar Menezes Silva
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil
| | - Karla Emília de Sá Rodrigues
- Departmento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efgênia, Belo Horizonte, MG, Brazil
| | - Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efigênia, Belo Horizonte, MG, Brazil.,Departmento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, CEP 30.130-100, Avenida Professor Alfredo Balena, nº190/sl 281, Santa Efgênia, Belo Horizonte, MG, Brazil
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11
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VanderVeen BN, Cardaci TD, McDonald SJ, Madero SS, Unger CA, Bullard BM, Enos RT, Velázquez KT, Kubinak JL, Fan D, Murphy EA. Obesity reduced survival with 5-fluorouracil and did not protect against chemotherapy-induced cachexia or immune cell cytotoxicity in mice. Cancer Biol Ther 2022; 23:1-15. [PMID: 35968771 PMCID: PMC9377261 DOI: 10.1080/15384047.2022.2108306] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/28/2022] [Accepted: 07/24/2022] [Indexed: 01/12/2023] Open
Abstract
Fluorouracil/5-flourouracil (5FU) is a first-line chemotherapy drug for many cancer types; however, its associated toxicities contribute to poor quality of life and reduced dose intensities negatively impacting patient prognosis. While obesity remains a critical risk factor for most cancers, our understanding regarding how obesity may impact chemotherapy's toxicities is extremely limited. C56BL/6 mice were given high fat (Obese) or standard diets (Lean) for 4 months and then subjected to three cycles of 5FU (5d-40 mg/kg Lean Mass, 9d rest) or PBS vehicle control. Shockingly, only 60% of Obese survived 3 cycles compared to 100% of Lean, and Obese lost significantly more body weight. Dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5FU catabolism, was reduced in obese livers. Total white blood cells, neutrophils, and lymphocytes were reduced in Obese 5FU compared to Lean 5FU and PBS controls. While adipocyte size was not affected by 5FU in Obese, skeletal muscle mass and myofibrillar cross section area were decreased following 5FU in Lean and Obese. Although adipose tissue inflammatory gene expression was not impacted by 5FU, distinct perturbations to skeletal muscle inflammatory gene expression and immune cell populations (CD45+ Immune cells, CD45+CD11b+CD68+ macrophages and CD45+CD11b+Ly6clo/int macrophage/monocytes) were observed in Obese only. Our evidence suggests that obesity induced liver pathologies and reduced DPD exacerbated 5FU toxicities. While obesity has been suggested to protect against cancer/chemotherapy-induced cachexia and other toxicities, our results demonstrate that obese mice are not protected, but rather show evidence of increased susceptibility to 5FU-induced cytotoxicity even when dosed for relative lean mass.
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Affiliation(s)
- Brandon N. VanderVeen
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Thomas D. Cardaci
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Sierra J. McDonald
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Sarah S. Madero
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Christian A. Unger
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Brooke M. Bullard
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Reilly T. Enos
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Kandy T. Velázquez
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Jason L. Kubinak
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - Daping Fan
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
| | - E. Angela Murphy
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine – Columbia, Columbia, SC, USA
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Li R, Dong F, Zhang L, Ni X, Lin G. Role of adipocytokines in endometrial cancer progression. Front Pharmacol 2022; 13:1090227. [PMID: 36578551 PMCID: PMC9791063 DOI: 10.3389/fphar.2022.1090227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Endometrial cancer is considered a significant barrier to increasing life expectancy and remains one of the most common malignant cancers among women in many countries worldwide. The increasing mortality rates are potentially proportional to the increasing obesity incidence. Adipose tissue secretes numerous adipocytokines, which may play important roles in endometrial cancer progression. In this scenario, we describe the role of adipocytokines in cell proliferation, cell invasion, cell adhesion, inflammation, angiogenesis, and anti-apoptotic action. A better understanding of the mechanisms of these adipocytokines may open up new therapeutic avenues for women with endometrial cancer. In the future, larger prospective studies focusing on adipocytokines and specific inhibitors should be directed at preventing the rapidly increasing prevalence of gynecological malignancies.
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Affiliation(s)
- Ran Li
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Fang Dong
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Ling Zhang
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Xiuqin Ni
- School of Health Sciences, Jiangsu Food and Pharmaceutical Science College, Huaian, China
| | - Guozhi Lin
- Department of Obstetrics and Gynecology, Second Affiliated Hospital to Shandong First Medical University, Taian, China,*Correspondence: Guozhi Lin,
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13
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Karalexi MA, Markozannes G, Tagkas CF, Katsimpris A, Tseretopoulou X, Tsilidis KK, Spector LG, Schüz J, Siahanidou T, Petridou ET, Ntzani EE. Nutritional Status at Diagnosis as Predictor of Survival from Childhood Cancer: A Review of the Literature. Diagnostics (Basel) 2022; 12:2357. [PMID: 36292046 PMCID: PMC9600212 DOI: 10.3390/diagnostics12102357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Few studies so far have examined the impact of nutritional status on the survival of children with cancer, with the majority of them focusing on hematological malignancies. We summarized published evidence reporting the association of nutritional status at diagnosis with overall survival (OS), event-free survival (EFS), relapse, and treatment-related toxicity (TRT) in children with cancer. Published studies on children with leukemia, lymphoma, and other solid tumors have shown that both under-nourished and over-nourished children at cancer diagnosis had worse OS and EFS. Particularly, the risk of death and relapse increased by 30-50% among children with leukemia with increased body mass index at diagnosis. Likewise, the risk of TRT was higher among malnourished children with osteosarcoma and Ewing sarcoma. Nutritional status seems to play a crucial role in clinical outcomes of children with cancer, thus providing a significant modifiable prognostic tool in childhood cancer management. Future studies with adequate power and longitudinal design are needed to further evaluate the association of nutritional status with childhood cancer outcomes using a more standardized definition to measure nutritional status in this population. The use of new technologies is expected to shed further light on this understudied area and give room to person-targeted intervention strategies.
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Affiliation(s)
- Maria A. Karalexi
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
- Hellenic Society for Social Pediatrics and Health Promotion, 11527 Athens, Greece
| | - Georgios Markozannes
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2BX, UK
| | - Christos F. Tagkas
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Andreas Katsimpris
- Hellenic Society for Social Pediatrics and Health Promotion, 11527 Athens, Greece
| | - Xanthippi Tseretopoulou
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
- Department of Pediatric Endocrinology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Konstantinos K. Tsilidis
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2BX, UK
| | - Logan G. Spector
- Department of Pediatrics, Division of Epidemiology & Clinical Research, University of Minnesota, Minneapolis, MN 55455, USA
| | - Joachim Schüz
- Section of Environment and Radiation, International Agency for Research on Cancer (IARC), 69372 Lyon, France
| | - Tania Siahanidou
- First Department of Pediatrics, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni Th. Petridou
- Hellenic Society for Social Pediatrics and Health Promotion, 11527 Athens, Greece
- Department of Hygiene, Epidemiology, and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelia E. Ntzani
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
- Center for Evidence Synthesis in Health, Brown University School of Public Health, Providence, RI 02903, USA
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14
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Khanlarkhani N, Azizi E, Amidi F, Khodarahmian M, Salehi E, Pazhohan A, Farhood B, Mortezae K, Goradel NH, Nashtaei MS. Metabolic risk factors of ovarian cancer: a review. JBRA Assist Reprod 2022; 26:335-347. [PMID: 34751020 PMCID: PMC9118962 DOI: 10.5935/1518-0557.20210067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 08/29/2021] [Indexed: 11/20/2022] Open
Abstract
Ovarian cancer continues to be the leading cause of death from gynecological cancers. Despite inconsistent results, patients with metabolic abnormalities, including obesity and diabetes mellitus (DM), have poorer outcomes, showing a correlation with ovarian cancer incidence and ovarian cancer survival. Since ovarian cancer is the most common cancer in women, and considering the increasing prevalence of obesity and DM, this paper reviews the literature regarding the relationship between the aforementioned metabolic derangements and ovarian cancer, with a focus on ovarian cancer incidence, mortality, and likely mechanisms behind them. Several systematic reviews and meta-analyses have shown that obesity is associated with a higher incidence and poorer survival in ovarian cancer. Although more studies are required to investigate the etiological relation of DM and ovarian cancer, sufficient biological evidence indicates poorer outcomes and shorter survival in DM women with ovarian cancer. A variety of pathologic factors may contribute to ovarian cancer risk, development, and survival, including altered adipokine expression, increased levels of circulating growth factors, altered levels of sex hormones, insulin resistance, hyperinsulinemia, and chronic inflammation. Thus, obesity and DM, as changeable risk factors, can be targeted for intervention to prevent ovarian cancer and improve its outcomes.
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Affiliation(s)
- Neda Khanlarkhani
- Department of Physiology and Pharmacology, Karolinska Institute, Sweden
| | - Elham Azizi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fardin Amidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahshad Khodarahmian
- Infertility department, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ensieh Salehi
- Department of Gynecology, School of Medicine, Fertility and Infertility Research Center, Dr. Ali Shariati Hospital, Shahid Mohammadi Hospital, Hormozgan University of Medical Sciences, Hormozgan, Iran
| | - Azar Pazhohan
- Infertility Center, Academic Center for Education, Culture and Research, East Azarbaijan, Tabriz, Iran. / Department of Midwifery, Urmia Branch, Islamic Azad University, Urmia, Iran
| | - Bagher Farhood
- Departments of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Keywan Mortezae
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shabani Nashtaei
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. / Infertility Department, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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15
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Assumpção JAF, Pasquarelli-do-Nascimento G, Duarte MSV, Bonamino MH, Magalhães KG. The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy. J Biomed Sci 2022; 29:12. [PMID: 35164764 PMCID: PMC8842976 DOI: 10.1186/s12929-022-00796-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
Obesity is nowadays considered a pandemic which prevalence's has been steadily increasingly in western countries. It is a dynamic, complex, and multifactorial disease which propitiates the development of several metabolic and cardiovascular diseases, as well as cancer. Excessive adipose tissue has been causally related to cancer progression and is a preventable risk factor for overall and cancer-specific survival, associated with poor prognosis in cancer patients. The onset of obesity features a state of chronic low-grade inflammation and secretion of a diversity of adipocyte-derived molecules (adipokines, cytokines, hormones), responsible for altering the metabolic, inflammatory, and immune landscape. The crosstalk between adipocytes and tumor cells fuels the tumor microenvironment with pro-inflammatory factors, promoting tissue injury, mutagenesis, invasion, and metastasis. Although classically established as a risk factor for cancer and treatment toxicity, recent evidence suggests mild obesity is related to better outcomes, with obese cancer patients showing better responses to treatment when compared to lean cancer patients. This phenomenon is termed obesity paradox and has been reported in different types and stages of cancer. The mechanisms underlying this paradoxical relationship between obesity and cancer are still not fully described but point to systemic alterations in metabolic fitness and modulation of the tumor microenvironment by obesity-associated molecules. Obesity impacts the response to cancer treatments, such as chemotherapy and immunotherapy, and has been reported as having a positive association with immune checkpoint therapy. In this review, we discuss obesity's association to inflammation and cancer, also highlighting potential physiological and biological mechanisms underlying this association, hoping to clarify the existence and impact of obesity paradox in cancer development and treatment.
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Affiliation(s)
| | | | - Mariana Saldanha Viegas Duarte
- Immunology and Tumor Biology Program - Research Coordination, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - Martín Hernan Bonamino
- Immunology and Tumor Biology Program - Research Coordination, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil
- Vice - Presidency of Research and Biological Collections (VPPCB), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil
| | - Kelly Grace Magalhães
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasília, DF, Brazil.
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16
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Charvat H, Freisling H, Noh H, Gaudet MM, Gunter MJ, Cross AJ, Tsilidis KK, Tjønneland A, Katzke V, Bergmann M, Agnoli C, Rylander C, Skeie G, Jakszyn P, Rosendahl AH, Sund M, Severi G, Tsugane S, Sawada N, Brenner H, Adami HO, Weiderpass E, Soerjomataram I, Arnold M. Excess Body Fatness during Early to Mid-Adulthood and Survival from Colorectal and Breast Cancer: A Pooled Analysis of Five International Cohort Studies. Cancer Epidemiol Biomarkers Prev 2022; 31:325-333. [PMID: 34782393 PMCID: PMC7612347 DOI: 10.1158/1055-9965.epi-21-0688] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/16/2021] [Accepted: 11/03/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Here, we explore the association between excess weight during early to mid-adulthood and survival in patients diagnosed with breast and colorectal cancer, using a pooled analysis of five cohort studies and study participants from 11 countries. METHODS Participant-level body mass index (BMI) trajectories were estimated by fitting a growth curve model using over 2 million repeated BMI measurements from close to 600,000 cohort participants. Cumulative measures of excess weight were derived. Data from over 23,000 patients with breast and colorectal cancer were subsequently analyzed using time-to-event models for death with the date of diagnosis as start of follow-up. Study-specific results were combined through a random effect meta-analysis. RESULTS We found a significant dose-response relationship (P trend = 0.013) between the average BMI during early and mid-adulthood and death from breast cancer, with a pooled HR of 1.31 (1.07-1.60) and the time to death shortened by 16% for average BMI above 25 kg/m2 compared with average BMI less than or equal to 22.5 kg/m2, respectively. Similar results were found for categories of cumulative time spent with excess weight. There was no association between excess body fatness during early to mid-adulthood and death in patients with colorectal cancer. CONCLUSIONS Excess body fatness during early to mid-adulthood is associated not only with an increased risk of developing cancer, but also with a lower survival in patients with breast cancer. IMPACT Our results emphasize the importance of public health policies aimed at reducing overweight during adulthood and inform future studies on the relationship between excess weight and cancer outcomes.
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Affiliation(s)
- Hadrien Charvat
- Cancer Surveillance Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Heinz Freisling
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Hwayoung Noh
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Mia M Gaudet
- Department of Population Sciences, American Cancer Society, Atlanta, Georgia
| | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Anne Tjønneland
- Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Verena Katzke
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Manuela Bergmann
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Claudia Agnoli
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Charlotta Rylander
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø (UiT), The Arctic University of Norway, Tromsø, Norway
| | - Guri Skeie
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø (UiT), The Arctic University of Norway, Tromsø, Norway
- Nutritional Epidemiology Group, School of Food and Nutrition, University of Leeds, Leeds, United Kingdom
| | - Paula Jakszyn
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Facultat Ciències Salut Blanquerna, Universitat Ramon Llull, Barcelona, Spain
| | - Ann H Rosendahl
- Department of Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden
| | - Malin Sund
- Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
| | - Gianluca Severi
- Center for Research in Epidemiology and Population Health, Institut Gustave Roussy, Villejuif, France
| | - Shoichiro Tsugane
- Epidemiology and Prevention Division, National Cancer Center, Japan, Tokyo
| | - Norie Sawada
- Epidemiology and Prevention Division, National Cancer Center, Japan, Tokyo
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hans-Olov Adami
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Clinical Effectiveness Research Group, Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Elisabete Weiderpass
- Director's Office, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Isabelle Soerjomataram
- Cancer Surveillance Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Melina Arnold
- Cancer Surveillance Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
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Del Grande M, Rizzo S, Nicolino GM, Colombo I, Rossi L, Manganaro L, Del Grande F. Computed Tomography-Based Body Composition in Patients With Ovarian Cancer: Association With Chemotoxicity and Prognosis. Front Oncol 2021; 11:718815. [PMID: 34868915 PMCID: PMC8634936 DOI: 10.3389/fonc.2021.718815] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/26/2021] [Indexed: 01/06/2023] Open
Abstract
Purpose To assess the association between computed tomography (CT)-derived quantitative measures of body composition profiling and chemotherapy-related complications, in terms of dose reduction, premature discontinuation of chemotherapy, and cycle delays in patients with ovarian cancer. Secondary purposes were to evaluate associations between sarcopenia and survival, and to evaluate differences in body composition profiling at baseline and after neoadjuvant chemotherapy. Materials and Methods The study population was retrospectively selected from a database of patients with newly diagnosed ovarian cancer (any stage) referred to our Institution between Feb 2011 and Mar 2020. Clinical data were recorded, and CT images at the level of the 3rd lumbar vertebra were stored. By using specific software, skeletal muscle area (SMA), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were extracted. Skeletal muscle index (SMI) was then calculated. Statistical analysis was performed by logistic regression models to identify body composition features predictive of dose reduction, premature end of chemotherapy, and cycle delays. Kaplan-Meier analyses were performed to assess overall survival (OS) and progression-free survival (PFS). The log-rank test was used to determine differences in OS and PFS between sarcopenic and non-sarcopenic patients. Wilcoxon test was performed to compare body composition features before and after neoadjuvant chemotherapy (NACT). Results Sixty-nine patients were included. A significant association was found between VAT and cycle delays (OR = 1.01, z = 2.01, 95% CI: 1.00–1.02, p < 0.05), between SMA and early discontinuation of chemotherapy (OR = 1.03, z = 2.10, 95% CI: 1.00–1.05, p < 0.05), and between mean SMD and cycle delays (OR = 0.92, z = −2.70, 95%CI: 0.87–0.98, p < 0.01). No significant difference emerged for OS in sarcopenic and non-sarcopenic patients, nor in CT body composition features before and after NACT. Conclusions In ovarian cancer patients, CT-derived body composition profiling might predict the risk of chemotoxicity. In particular, VAT and SMD are associated with chemotherapy cycle delays, and SMA with early discontinuation of chemotherapy.
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Affiliation(s)
- Maria Del Grande
- Service of Medical Oncology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Stefania Rizzo
- Istituto di Imaging della Svizzera Italiana (IIMSI), Ente Ospedaliero Cantonale, Lugano, Switzerland.,Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Lugano, Switzerland
| | | | - Ilaria Colombo
- Service of Medical Oncology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Lorenzo Rossi
- Service of Medical Oncology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Lucia Manganaro
- Department of Radiological, Oncological and Pathological Sciences, University of Rome Sapienza, Rome, Italy
| | - Filippo Del Grande
- Istituto di Imaging della Svizzera Italiana (IIMSI), Ente Ospedaliero Cantonale, Lugano, Switzerland.,Facoltà di Scienze Biomediche, Università della Svizzera Italiana, Lugano, Switzerland
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18
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Hoy AJ, Nagarajan SR, Butler LM. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat Rev Cancer 2021; 21:753-766. [PMID: 34417571 DOI: 10.1038/s41568-021-00388-4] [Citation(s) in RCA: 203] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/01/2021] [Indexed: 02/07/2023]
Abstract
Fatty acid metabolism is known to support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage and catabolism. More recently, the role of membrane fatty acid composition, for example, ratios of saturated, monounsaturated and polyunsaturated fatty acids, in promoting cell survival while limiting lipotoxicity and ferroptosis has been increasingly appreciated. Alongside these insights, it has become clear that tumour cells exhibit plasticity with respect to fatty acid metabolism, responding to extratumoural and systemic metabolic signals, such as obesity and cancer therapeutics, to promote the development of aggressive, treatment-resistant disease. Here, we describe cellular fatty acid metabolic changes that are connected to therapy resistance and contextualize obesity-associated changes in host fatty acid metabolism that likely influence the local tumour microenvironment to further modify cancer cell behaviour while simultaneously creating potential new vulnerabilities.
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Affiliation(s)
- Andrew J Hoy
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
| | - Shilpa R Nagarajan
- School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom
| | - Lisa M Butler
- Adelaide Medical School and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, South Australia, Australia
- South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
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Abstract
Despite the evidence supporting the relevance of obesity and obesity‐associated disorders in the development, management, and prognosis of various cancers, obesity rates continue to increase worldwide. Growing evidence supports the involvement of obesity in the development of gynecologic malignancies. This article explores the molecular basis governing the alteration of hallmarks of cancer in the development of obesity‐related gynecologic malignancies encompassing cervical, endometrial, and ovarian cancers. We highlight specific examples of how development, management, and prognosis are affected for each cancer, incorporate current knowledge on complementary approaches including lifestyle interventions to improve patient outcomes, and highlight how new technologies are helping us better understand the biology underlying this neglected pandemic. This review focuses on how obesity impacts cancer hallmarks in gynecologic malignancies, thus affecting the diagnosis, management, treatment, and prognosis of these diseases.
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Affiliation(s)
- Ignacio A. Wichmann
- Division of Gynecology and ObstetricsSchool of MedicinePontificia Universidad Católica de ChileSantiagoChile
- Department of ObstetricsSchool of MedicinePontificia Universidad Católica de ChileSantiagoChile
- Advanced Center for Chronic DiseasesPontificia Universidad Católica de ChileSantiagoChile
| | - Mauricio A. Cuello
- Division of Gynecology and ObstetricsSchool of MedicinePontificia Universidad Católica de ChileSantiagoChile
- Department of GynecologySchool of MedicinePontificia Universidad Católica de ChileSantiagoChile
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20
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Kiesel L, Eichbaum C, Baumeier A, Eichbaum M. Obesity Epidemic-The Underestimated Risk of Endometrial Cancer. Cancers (Basel) 2020; 12:E3860. [PMID: 33371216 PMCID: PMC7767192 DOI: 10.3390/cancers12123860] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 12/24/2022] Open
Abstract
Endometrial cancer (EC) is the most frequently observed malignant gynecologic disease in developed countries. There is a strong association between the established risk factor obesity and the incidence of EC. Furthermore, the rate of women with a body mass index (BMI) > 30 kg/m2 is increasing worldwide, correspondingly leading to a higher prevalence of EC. Understanding the adipose tissue as an endocrine organ, elementary pathophysiological pathways of tumorigenesis have been revealed. This includes the fundamental role of hyperglycemia, insulin resistance, and hyperestrogenemia, as well as interactions with a chronic proinflammatory microenvironment. Therapeutic options potentially include metformin or bariatric surgery. Moreover, changes in individual lifestyle such as weight reduction, physical activity, and an awareness of healthy nutrition are effective in preventing the disease.
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Affiliation(s)
- Ludwig Kiesel
- Department of Gynecology and Obstetrics, University of Münster Medical School, Albert-Schweitzer-Campus 1, 48149 Münster, Germany;
| | - Christine Eichbaum
- Department of Gynecology and Obstetrics, University of Frankfurt Medical School, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany;
| | - Ariane Baumeier
- Department of Gynecology and Obstetrics, University of Münster Medical School, Albert-Schweitzer-Campus 1, 48149 Münster, Germany;
| | - Michael Eichbaum
- Department of Gynecology and Obstetrics, Helios Dr. Horst-Schmidt-Kliniken Wiesbaden, Ludwig-Erhard-Str. 100, 65199 Wiesbaden, Germany
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21
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Kölbl H, Bartl T. Obesity in Gynecologic Oncology. Geburtshilfe Frauenheilkd 2020; 80:1205-1211. [PMID: 33293728 PMCID: PMC7714555 DOI: 10.1055/a-1124-7139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 07/25/2020] [Indexed: 12/31/2022] Open
Abstract
The decades-long global obesity epidemic has resulted in steady increase in the incidence of obesity-related malignancies. The associated diagnostic and therapeutic implications present a clinical challenge for gynecologic oncology treatment strategies. Recent studies have provided solid evidence for an independent, linear, positive correlation between a pathologically increased body mass index and the probability of developing endometrial or postmenopausal breast cancer. The pathogenesis is complex and the subject of current research. Proposed causes include pathologically increased serum levels of sexual steroids and adiponectin, obesity-induced insulin resistance, and systemic inflammatory processes. The scientific evidence for an association between obesity and other gynecological malignancies is, however, less solid. The clinical relevance of obesity as a risk factor for epithelial ovarian cancer, cervical cancer and vulvar cancer appears to be negligible.
Nevertheless, obesity appears to have a negative impact on prognosis and oncologic outcomes for all gynecological cancers. Whether or not this effect can be interpreted as correlative or causal is still a subject of ongoing debate.
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Affiliation(s)
- Heinz Kölbl
- Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie, Universitätsklinik für Frauenheilkunde, Medizinische Universität Wien, Wien, Austria
| | - Thomas Bartl
- Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie, Universitätsklinik für Frauenheilkunde, Medizinische Universität Wien, Wien, Austria
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22
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Asante EC, Pallegar NK, Hoffmann AJ, Viloria-Petit AM, Christian SL. Adipose Tissue from Lean and Obese Mice Induces a Mesenchymal to Epithelial Transition-Like Effect in Triple Negative Breast Cancers Cells Grown in 3-Dimensional Culture. Int J Mol Sci 2020; 21:E6439. [PMID: 32899433 PMCID: PMC7503907 DOI: 10.3390/ijms21176439] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/31/2020] [Accepted: 09/01/2020] [Indexed: 01/01/2023] Open
Abstract
Breast cancer is the second leading cause of cancer-related mortality among women globally with obesity being one risk factor. Obese breast cancer patients have at least a 30% increased risk of death from breast cancer compared to non-obese breast cancer patients because they present with larger tumors and generally have increased rates of metastasis. Moreover, obese breast cancer patients respond more poorly to treatment compared to non-obese patients, particularly pre-menopausal women diagnosed with triple negative breast cancer (TNBC). To help understand the molecular mechanisms underlying the increased metastasis associated with obesity, we previously established a three-dimensional culture system that permits the co-culture of adipocytes and TNBC cells in a manner that mimics an in vivo milieu. Using this system, we demonstrate that white adipose tissue from both lean and obese mice can induce a partial mesenchymal-to-epithelial transition (MET). Triple negative breast cancer cells adopt an epithelial morphology and have an increased expression of some epithelial markers, but they maintain the expression of mesenchymal markers, furnishing the breast cancer cells with hybrid properties that are associated with more aggressive tumors. Thus, these data suggest that adipose tissue has the potential to promote secondary tumor formation in lean and obese women. Further work is needed to determine if targeting the partial MET induced by adipose tissue could reduce metastasis.
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Affiliation(s)
- Emmanuel C. Asante
- Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X9, Canada; (E.C.A.); (N.K.P.); (A.J.H.)
| | - Nikitha K. Pallegar
- Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X9, Canada; (E.C.A.); (N.K.P.); (A.J.H.)
| | - Alica J. Hoffmann
- Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X9, Canada; (E.C.A.); (N.K.P.); (A.J.H.)
| | - Alicia M. Viloria-Petit
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada;
| | - Sherri L. Christian
- Department of Biochemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X9, Canada; (E.C.A.); (N.K.P.); (A.J.H.)
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23
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Kolb R, Zhang W. Obesity and Breast Cancer: A Case of Inflamed Adipose Tissue. Cancers (Basel) 2020; 12:E1686. [PMID: 32630445 PMCID: PMC7352736 DOI: 10.3390/cancers12061686] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/09/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients.
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Affiliation(s)
- Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, Gainesville, FL 32610, USA;
- University of Florida Health Cancer Center, Gainesville, FL 32610, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, Gainesville, FL 32610, USA;
- University of Florida Health Cancer Center, Gainesville, FL 32610, USA
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24
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Aleixo GFP, Shachar SS, Deal AM, Nyrop KA, Muss HB, Chen YT, Yu H, Williams GR. The association of body composition parameters and adverse events in women receiving chemotherapy for early breast cancer. Breast Cancer Res Treat 2020; 182:631-642. [PMID: 32519169 DOI: 10.1007/s10549-020-05731-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/05/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Body composition metrics as predictors of adverse events are a growing area of interest in oncology research. One barrier to the use of these metrics in clinical practice is the lack of standardized cut points for identifying patients with at-risk body composition profiles. We examined the association of chemotherapy adverse events with several body composition measures, using alternative cut points from published studies. METHODS This is a retrospective study of women diagnosed with early breast cancer (EBC). Axial computerized tomography (CT) images from lumbar L3 segments were analyzed for the following body composition measures: myosteatosis (low Skeletal Muscle Density/SMD), sarcopenia (low Skeletal Muscle Index/SMI), and high Visceral Adipose Tissue (VAT). Adverse events during chemotherapy were dose reduction, early treatment discontinuation, and hospitalization. Log-binomial modeling was used to evaluate associations between body composition measures at different cut points with adverse events, adjusting for age, race, Body Mass Index/BMI, and comorbidities. Relative risks were reported as the measure of association. RESULTS In a sample of 338 women, mean age was 51, 14% were age 65 or older, 32% were non-white, 40% had obesity (/BMI ≥ 30 kg/m2), and mean number of comorbidities was 1.56. In multivariable analysis (MV), all three SMD cut points for myosteatosis had significant associations with total number of adverse events, as well as different cut points having significant associations with either dose reduction, early treatment discontinuation or hospitalization. SMI and VAT were not significant in the MV analysis; however, in some models, age and total comorbidities were significant for adverse events. CONCLUSIONS Among CT-derived measures of body composition, myosteatosis determined at any of three SMD cut points was associated with total and individual adverse events during chemotherapy for early breast cancer.
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Affiliation(s)
- G F P Aleixo
- Division of Hematology-Oncology, University of North Carolina at Chapel Hill, 170 Manning Dr., Chapel Hill, NC, USA. .,Universidade Do Oeste Paulista (UNOESTE), Presidente Prudente, SP, Brazil.
| | - S S Shachar
- Ruth and Bruce Rappaport Faculty of Medicine at Technion, Haifa, Israel
| | - A M Deal
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - K A Nyrop
- Division of Hematology-Oncology, University of North Carolina at Chapel Hill, 170 Manning Dr., Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - H B Muss
- Division of Hematology-Oncology, University of North Carolina at Chapel Hill, 170 Manning Dr., Chapel Hill, NC, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Y T Chen
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - H Yu
- Division of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - G R Williams
- Division of Hematology/Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA
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25
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Woodall MJ, Neumann S, Campbell K, Pattison ST, Young SL. The Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy. Cancers (Basel) 2020; 12:E1230. [PMID: 32422865 PMCID: PMC7281442 DOI: 10.3390/cancers12051230] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/29/2020] [Accepted: 05/12/2020] [Indexed: 12/30/2022] Open
Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient's own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy.
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Affiliation(s)
- Matthew J. Woodall
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (M.J.W.); (S.N.); (K.C.)
| | - Silke Neumann
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (M.J.W.); (S.N.); (K.C.)
| | - Katrin Campbell
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (M.J.W.); (S.N.); (K.C.)
| | - Sharon T. Pattison
- Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand;
| | - Sarah L. Young
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand; (M.J.W.); (S.N.); (K.C.)
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney 2006, Australia
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26
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Withers SB, Dewhurst T, Hammond C, Topham CH. MiRNAs as Novel Adipokines: Obesity-Related Circulating MiRNAs Influence Chemosensitivity in Cancer Patients. Noncoding RNA 2020; 6:ncrna6010005. [PMID: 31979312 PMCID: PMC7151601 DOI: 10.3390/ncrna6010005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/08/2020] [Accepted: 01/11/2020] [Indexed: 12/12/2022] Open
Abstract
Adipose tissue is an endocrine organ, capable of regulating distant physiological processes in other tissues via the release of adipokines into the bloodstream. Recently, circulating adipose-derived microRNAs (miRNAs) have been proposed as a novel class of adipokine, due to their capacity to regulate gene expression in tissues other than fat. Circulating levels of adipokines are known to be altered in obese individuals compared with typical weight individuals and are linked to poorer health outcomes. For example, obese individuals are known to be more prone to the development of some cancers, and less likely to achieve event-free survival following chemotherapy. The purpose of this review was twofold; first to identify circulating miRNAs which are reproducibly altered in obesity, and secondly to identify mechanisms by which these obesity-linked miRNAs might influence the sensitivity of tumors to treatment. We identified 8 candidate circulating miRNAs with altered levels in obese individuals (6 increased, 2 decreased). A second literature review was then performed to investigate if these candidates might have a role in mediating resistance to cancer treatment. All of the circulating miRNAs identified were capable of mediating responses to cancer treatment at the cellular level, and so this review provides novel insights which can be used by future studies which aim to improve obese patient outcomes.
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Affiliation(s)
- Sarah B. Withers
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
- Salford Royal Foundation Trust, Clinical Sciences Building, Stott Lane, Salford M6 8HD, UK
| | - Toni Dewhurst
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
| | - Chloe Hammond
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
| | - Caroline H. Topham
- Biomedical Research Centre, School of Science, Engineering and Environment, Peel Building, University of Salford, Salford M5 4WT, UK; (S.B.W.); (T.D.); (C.H.)
- Correspondence: ; Tel.: +44-(0)-161-295-4292
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Jiramongkol Y, Lam EWF. Multifaceted Oncogenic Role of Adipocytes in the Tumour Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1219:125-142. [PMID: 32130697 DOI: 10.1007/978-3-030-34025-4_7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Obesity has for decades been recognised as one of the major health concerns. Recently accumulated evidence has established that obesity or being overweight is strongly linked to an increased risk of cancer. However, it is still not completely clear how adipose tissue (fat), along with other stromal connective tissues and cells, contribute to tumour initiation and progression. In the tumour microenvironment, the adipose tissue cells, in particular the adipocytes, secrete a number of adipokines, including growth factors, hormones, collagens, fatty acids, and other metabolites as well as extracellular vesicles to shape and condition the tumour and its microenvironment. In fact, the adipocytes, through releasing these factors and materials, can directly and indirectly facilitate cancer cell proliferation, apoptosis, metabolism, angiogenesis, metastasis and even chemotherapy resistance. In this chapter, the multidimensional role played by adipocytes, a major and functional component of the adipose tissue, in promoting cancer development and progression within the tumour microenvironment will be discussed.
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Affiliation(s)
- Yannasittha Jiramongkol
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
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28
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Corrias G, Sawan P, Mahmood U, Zheng J, Capanu M, Salvatore M, Spinato G, Saba L, Mannelli L. Dual energy computed tomography analysis in cancer patients: What factors affect iodine concentration in contrast enhanced studies? Eur J Radiol 2019; 120:108698. [PMID: 31600640 DOI: 10.1016/j.ejrad.2019.108698] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 08/28/2019] [Accepted: 09/26/2019] [Indexed: 12/15/2022]
Abstract
PURPOSE The aim of the study is to explore the patient's and scan's parameters that affect the iodine concentration in the abdomen using dual energy computed tomography (DECT) in an oncologic population. METHOD This is a retrospective study with consecutive patients with different cancers who underwent a single-source DECT (ssDECT) examinations at our institution between years 2015 and 2017. On axial IODINE images, the radiologist manually drew a circular ROI along the inner contour of the aorta. Mean iodine concentration and ROI areas were recorded. Body mass index for every patient was recorded. Descriptive statistics were summarized for iodine concentration and patient/scan characteristics. Linear regression was used to examine associations between iodine concentration in aorta and studied characteristics. Statistical significance was set at a p value < 0.05. RESULTS The univariate analysis, showed a statistically significant association between iodine concentration within the aorta and the area of ROI (Estimated Coefficient β: -0.013), the rate of injection (Estimated Coefficient β: 2.09), the acquisition time (Estimated Coefficient β: -0.195). In multivariable analysis iodine concentration in the aorta increased with higher rate of injection (4 ml/sec), smaller ROI area and lower BMI. CONCLUSION Our results showed how iodine concentration is highly dependent on some intrinsic and extrinsic parameters of the examination. These parameters should be taken into account since lower concentration of iodine decrease contrast-to-noise ratio, and in longitudinal follow up studies, they would affect iodine quantitive assessments in cancer patients with frequent chemotherapy-induced variations in BMI and cardiac function.
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Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA; Department of Radiology, University of Cagliari, Via Università, 40, 09124, Cagliari, CA, Italy
| | - Peter Sawan
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Usman Mahmood
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Junting Zheng
- Department of Statistics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Marinela Capanu
- Department of Statistics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | | | - Giacomo Spinato
- Department of Neurosciences, Section of Otolaryngology and Regional Centre for Head and Neck Cancer, University of Padova, Treviso, Italy; Department of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova, Padova, Italy
| | - Luca Saba
- Department of Radiology, University of Cagliari, Via Università, 40, 09124, Cagliari, CA, Italy
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Zamorano AS, Hagemann AR, Morrison L, Lee JA, Liao LM, Brinton LA, Park Y, Toriola AT. Pre-diagnosis body mass index, physical activity and ovarian cancer mortality. Gynecol Oncol 2019; 155:105-111. [DOI: 10.1016/j.ygyno.2019.07.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/18/2019] [Accepted: 07/28/2019] [Indexed: 12/24/2022]
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Shepshelovich D, Xu W, Lu L, Fares A, Yang P, Christiani D, Zhang J, Shiraishi K, Ryan BM, Chen C, Schwartz AG, Tardon A, Wu X, Schabath MB, Teare MD, Le Marchand L, Zhang ZF, Field JK, Brenner H, Diao N, Xie J, Kohno T, Harris CC, Wenzlaff AS, Fernandez-Tardon G, Ye Y, Taylor F, Wilkens LR, Davies M, Liu Y, Barnett MJ, Goodman GE, Morgenstern H, Holleczek B, Brown MC, Liu G, Hung RJ. Body Mass Index (BMI), BMI Change, and Overall Survival in Patients With SCLC and NSCLC: A Pooled Analysis of the International Lung Cancer Consortium. J Thorac Oncol 2019; 14:1594-1607. [PMID: 31163278 PMCID: PMC6734935 DOI: 10.1016/j.jtho.2019.05.031] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 04/27/2019] [Accepted: 05/21/2019] [Indexed: 01/09/2023]
Abstract
INTRODUCTION The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.
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Affiliation(s)
- Daniel Shepshelovich
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto, Toronto, Ontario, Canada; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Wei Xu
- Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Lin Lu
- Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Aline Fares
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto, Toronto, Ontario, Canada
| | | | - David Christiani
- Environmental Health Department, Harvard TH Chan School of Public Health and Harvard Medical School, Boston, Massachusetts
| | - Jie Zhang
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Research Institute, Tokyo, Japan
| | - Brid M Ryan
- Centre for Cancer Research, National Institutes of Health, Bethesda, Maryland
| | - Chu Chen
- Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology and Department of Otolaryngology: Head and Neck Surgery, University of Washington, Seattle, Washington
| | - Ann G Schwartz
- Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | | | - Xifeng Wu
- University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - M Dawn Teare
- University of Sheffield, Sheffield, United Kingdom
| | | | - Zuo-Feng Zhang
- University of California Los Angeles School of Public Health, California
| | - John K Field
- The Roy Castle Lung Cancer Programme, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, United Kingdom
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nancy Diao
- Environmental Health Department, Harvard TH Chan School of Public Health and Harvard Medical School, Boston, Massachusetts
| | - Juntao Xie
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Research Institute, Tokyo, Japan
| | - Curtis C Harris
- Centre for Cancer Research, National Institutes of Health, Bethesda, Maryland
| | - Angela S Wenzlaff
- Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | | | - Yuanqing Ye
- University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fiona Taylor
- University of Sheffield, Sheffield, United Kingdom
| | | | - Michael Davies
- The Roy Castle Lung Cancer Programme, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, United Kingdom
| | - Yi Liu
- PLA Hospital, Beijing, China
| | - Matt J Barnett
- Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | | - Hal Morgenstern
- Departments of Epidemiology and Environmental Health Sciences, School of Public Health and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan
| | | | - M Catherine Brown
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto, Toronto, Ontario, Canada
| | - Geoffrey Liu
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre; University of Toronto, Toronto, Ontario, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
| | - Rayjean J Hung
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
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31
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Fortner RT, Poole EM, Wentzensen NA, Trabert B, White E, Arslan AA, Patel AV, Setiawan VW, Visvanathan K, Weiderpass E, Adami HO, Black A, Bernstein L, Brinton LA, Buring J, Clendenen TV, Fournier A, Fraser G, Gapstur SM, Gaudet MM, Giles GG, Gram IT, Hartge P, Hoffman-Bolton J, Idahl A, Kaaks R, Kirsh VA, Knutsen S, Koh WP, Lacey JV, Lee IM, Lundin E, Merritt MA, Milne RL, Onland-Moret NC, Peters U, Poynter JN, Rinaldi S, Robien K, Rohan T, Sánchez MJ, Schairer C, Schouten LJ, Tjonneland A, Townsend MK, Travis RC, Trichopoulou A, van den Brandt PA, Vineis P, Wilkens L, Wolk A, Yang HP, Zeleniuch-Jacquotte A, Tworoger SS. Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium. Int J Cancer 2019. [PMID: 30561796 DOI: 10.1002/ijc.32075] [] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
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Affiliation(s)
- Renée T Fortner
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Elizabeth M Poole
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Nicolas A Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Britton Trabert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Emily White
- Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Alan A Arslan
- New York University School of Medicine, New York, NY
| | - Alpa V Patel
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | | | | | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.,Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Genetic Epidemiology Group, Folkhälsan Research Center, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hans-Olov Adami
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Amanda Black
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | | | - Louise A Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Julie Buring
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | | | - Agnès Fournier
- CESP "Health across Generations," INSERM, Univ Paris-Sud, UVSQ, Univ Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
| | | | - Susan M Gapstur
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - Mia M Gaudet
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - Graham G Giles
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.,Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Inger T Gram
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | | | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Victoria A Kirsh
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | | | - Woon-Puay Koh
- Health Services and Systems Research, Duke-NUS Medical School Singapore, Singapore
| | | | - I-Min Lee
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Eva Lundin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Melissa A Merritt
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI.,Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, United Kingdom
| | - Roger L Milne
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.,Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - N Charlotte Onland-Moret
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Jenny N Poynter
- Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Sabina Rinaldi
- International Agency for Research on Cancer, Lyon, France
| | - Kim Robien
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, D.C
| | - Thomas Rohan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
| | - Maria-José Sánchez
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.,CIBER de Epidemiología y Salud Pública (CIBERESP), Spain
| | - Catherine Schairer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Leo J Schouten
- GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | | | - Mary K Townsend
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece.,WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Greece
| | - Piet A van den Brandt
- GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Paolo Vineis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, United Kingdom.,HuGeF Foundation, Torino, Italy
| | - Lynne Wilkens
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hannah P Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | | | - Shelley S Tworoger
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL
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32
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Fortner RT, Poole EM, Wentzensen NA, Trabert B, White E, Arslan AA, Patel AV, Setiawan VW, Visvanathan K, Weiderpass E, Adami HO, Black A, Bernstein L, Brinton LA, Buring J, Clendenen TV, Fournier A, Fraser G, Gapstur SM, Gaudet MM, Giles GG, Gram IT, Hartge P, Hoffman-Bolton J, Idahl A, Kaaks R, Kirsh VA, Knutsen S, Koh WP, Lacey JV, Lee IM, Lundin E, Merritt MA, Milne RL, Onland-Moret NC, Peters U, Poynter JN, Rinaldi S, Robien K, Rohan T, Sánchez MJ, Schairer C, Schouten LJ, Tjonneland A, Townsend MK, Travis RC, Trichopoulou A, van den Brandt PA, Vineis P, Wilkens L, Wolk A, Yang HP, Zeleniuch-Jacquotte A, Tworoger SS. Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium. Int J Cancer 2019; 145:58-69. [PMID: 30561796 PMCID: PMC6488363 DOI: 10.1002/ijc.32075] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/19/2018] [Accepted: 11/05/2018] [Indexed: 12/21/2022]
Abstract
Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
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Affiliation(s)
- Renée T. Fortner
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Elizabeth M. Poole
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Nicolas A. Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington D.C., USA
| | - Britton Trabert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington D.C., USA
| | - Emily White
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Alan A. Arslan
- New York University School of Medicine, New York, NY, USA
| | - Alpa V. Patel
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | | | - Kala Visvanathan
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
- Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Genetic Epidemiology Group, Folkhälsan Research Center; Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hans-Olov Adami
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Amanda Black
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington D.C., USA
| | | | - Louise A. Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington D.C., USA
| | - Julie Buring
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Agnès Fournier
- CESP “Health across Generations”, INSERM, Univ Paris-Sud, UVSQ, Univ Paris-Saclay, Villejuif, France
- Gustave Roussy, Villejuif, France
| | | | - Susan M. Gapstur
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | - Mia M. Gaudet
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | - Graham G. Giles
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Inger T. Gram
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington D.C., USA
| | | | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Victoria A. Kirsh
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | | | - Woon-Puay Koh
- Health Services and Systems Research, Duke-NUS Medical School Singapore, Singapore
| | | | - I-Min Lee
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Eva Lundin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Melissa A. Merritt
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom
| | - Roger L. Milne
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - N. Charlotte Onland-Moret
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Ulrike Peters
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jenny N. Poynter
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sabina Rinaldi
- International Agency for Research on Cancer, Lyon, France
| | - Kim Robien
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, DC
| | - Thomas Rohan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Maria-José Sánchez
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Spain
| | - Catherine Schairer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington D.C., USA
| | - Leo J. Schouten
- GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | | | - Mary K. Townsend
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Ruth C. Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece
- WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Greece
| | - Piet A. van den Brandt
- GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Paolo Vineis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom
- HuGeF Foundation, Torino, Italy
| | - Lynne Wilkens
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hannah P. Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington D.C., USA
| | | | - Shelley S. Tworoger
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
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33
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Fortner RT, Poole EM, Wentzensen NA, Trabert B, White E, Arslan AA, Patel AV, Setiawan VW, Visvanathan K, Weiderpass E, Adami HO, Black A, Bernstein L, Brinton LA, Buring J, Clendenen TV, Fournier A, Fraser G, Gapstur SM, Gaudet MM, Giles GG, Gram IT, Hartge P, Hoffman-Bolton J, Idahl A, Kaaks R, Kirsh VA, Knutsen S, Koh WP, Lacey JV, Lee IM, Lundin E, Merritt MA, Milne RL, Onland-Moret NC, Peters U, Poynter JN, Rinaldi S, Robien K, Rohan T, Sánchez MJ, Schairer C, Schouten LJ, Tjonneland A, Townsend MK, Travis RC, Trichopoulou A, van den Brandt PA, Vineis P, Wilkens L, Wolk A, Yang HP, Zeleniuch-Jacquotte A, Tworoger SS. Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium. Int J Cancer 2019. [PMID: 30561796 DOI: 10.1002/ijc.32075]+[] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
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Affiliation(s)
- Renée T Fortner
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Elizabeth M Poole
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Nicolas A Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Britton Trabert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Emily White
- Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Alan A Arslan
- New York University School of Medicine, New York, NY
| | - Alpa V Patel
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | | | | | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.,Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Genetic Epidemiology Group, Folkhälsan Research Center, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hans-Olov Adami
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Amanda Black
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | | | - Louise A Brinton
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Julie Buring
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | | | - Agnès Fournier
- CESP "Health across Generations," INSERM, Univ Paris-Sud, UVSQ, Univ Paris-Saclay, Villejuif, France.,Gustave Roussy, Villejuif, France
| | | | - Susan M Gapstur
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - Mia M Gaudet
- Epidemiology Research Program, American Cancer Society, Atlanta, GA
| | - Graham G Giles
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.,Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Inger T Gram
- Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | | | - Annika Idahl
- Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Victoria A Kirsh
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | | | - Woon-Puay Koh
- Health Services and Systems Research, Duke-NUS Medical School Singapore, Singapore
| | | | - I-Min Lee
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Eva Lundin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Melissa A Merritt
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI.,Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, United Kingdom
| | - Roger L Milne
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.,Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - N Charlotte Onland-Moret
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Jenny N Poynter
- Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - Sabina Rinaldi
- International Agency for Research on Cancer, Lyon, France
| | - Kim Robien
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, George Washington University, Washington, D.C
| | - Thomas Rohan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY
| | - Maria-José Sánchez
- Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.,CIBER de Epidemiología y Salud Pública (CIBERESP), Spain
| | - Catherine Schairer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | - Leo J Schouten
- GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | | | - Mary K Townsend
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece.,WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept. of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Greece
| | - Piet A van den Brandt
- GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Paolo Vineis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, United Kingdom.,HuGeF Foundation, Torino, Italy
| | - Lynne Wilkens
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hannah P Yang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Washington, D.C
| | | | - Shelley S Tworoger
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.,Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL
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Bendifallah S, Ilenko A, Daraï E. High risk endometrial cancer: Clues towards a revision of the therapeutic paradigm. J Gynecol Obstet Hum Reprod 2019; 48:863-871. [PMID: 31176047 DOI: 10.1016/j.jogoh.2019.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 05/16/2019] [Accepted: 06/04/2019] [Indexed: 11/18/2022]
Abstract
INTRODUCTION Endometrial cancer (EC) is a major cause of mortality worldwide with nearly 200 000 cases diagnosed annually. The recent ESMO-ESGO-ESTRO guidelines include a new classification defining a heterogeneous high-risk group of recurrence (HR) comprising: (i) endometrioid (type 1) FIGO stage IB grade 3 tumors (type 1/G3ECs), (ii) non-endometrioid tumors (type 2) and (iii) advanced stages whatever the histological type (Colombo et al., 2016). AREAS COVERED The aim of this review is to summarize current evidence for therapeutic approaches in HR-EC according to the updated ESMO-ESGO-ESTRO classification by discussing the following issues: i) HR-EC heterogeneity, (ii) prognostic factors and current classification, and (iii) optimal staging strategies (site and extent) and the role of adjuvant treatment. EXPERT COMMENTARY HR-EC treatment is based on surgery, radiation therapy, brachytherapy, and chemotherapy, either alone or sequentially, in combination with other treatments depending on disease stage, histological grade and risk group. Specific trials are needed to establish the role of systematic pelvic and paraaortic lymphadenectomy, adjuvant therapies and targeted drugs. Although molecular characterization has been reported to customize therapeutic strategies and thereby improve therapeutic outcomes in EC, none of the targeted agents investigated (antiangiogenic and mTOR/PI3K pathway inhibitor agents) have resulted in a change in clinical practice in HR-EC.
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Affiliation(s)
- S Bendifallah
- Department of Obstetrics and Gynaecology, Tenon University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne Université, Institut Universitaire de Cancérologie (IUC), France; INSERM UMR S 938, Sorbonne université, Paris 6, France
| | - A Ilenko
- Department of Obstetrics and Gynaecology, Tenon University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne Université, Institut Universitaire de Cancérologie (IUC), France.
| | - E Daraï
- Department of Obstetrics and Gynaecology, Tenon University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne Université, Institut Universitaire de Cancérologie (IUC), France; INSERM UMR S 938, Sorbonne université, Paris 6, France
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35
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Bouleftour W, Mery B, Chanal E, Rowinski E, Viard A, Forges F, Fournel P, Rivoirard R. Obesity and chemotherapy administration: between empiric and mathematic method review. Acta Oncol 2019; 58:880-887. [PMID: 30907190 DOI: 10.1080/0284186x.2019.1585942] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Obesity is a major risk factor for chronic disease and cancer development. Therapeutic management of obese patients with cancer is a real challenge for physician because of the alteration of antineoplastic pharmacokinetics parameters in this population. In routine clinical practices, chemotherapy doses in obese patients are arbitrarily capped or adjusted to an ideal weight to minimize excessive toxicities. Material and methods: The main goal of this review is to describe the current state of knowledge concerning the correlation between the adjustment of BSA (capping or ideal weight) and the rates of global toxicities and survival outcomes in obese patients under chemotherapy in different types of cancer. We searched in the Medline database (via PubMed) in order to identify all publications of literature reviews whose subject chemotherapy dosing in obese population. Results: Only a single study was pointing toward increased of global toxicities of full weight dosing. Furthermore, some studies suggests that the practice of limiting doses in overweight and obese patients may negatively influence the quality of care and outcomes in a constantly increasing population. Conclusion: This review highlights the lack of prospective studies focusing on chemotherapy methods of administration in obese patients. At this time, there is no prospective study comparing capping and full weight dose chemotherapy administration in obese patient population.
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Affiliation(s)
- W. Bouleftour
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
| | - B. Mery
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
| | - E. Chanal
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
| | - E. Rowinski
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
| | - A. Viard
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
| | - F. Forges
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
| | - P. Fournel
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
| | - R. Rivoirard
- Département d’oncologie médicale, Institut de cancérologie Lucien Newirth, Saint Priest en Jarez, France
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36
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Guo H, Guo J, Xie W, Yuan L, Sheng X. The role of vitamin D in ovarian cancer: epidemiology, molecular mechanism and prevention. J Ovarian Res 2018; 11:71. [PMID: 30157901 PMCID: PMC6114234 DOI: 10.1186/s13048-018-0443-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 08/15/2018] [Indexed: 12/19/2022] Open
Abstract
Vitamin D is a fat-soluble prohormone best known for its role in maintaining calcium homeostasis. Large numbers of epidemiological studies have shown that vitamin D plays an important role in cancer prevention by regulating cellular proliferation and metabolism. Studies of the cellular mechanism of vitamin D in ovarian cancer strongly suggest that it exhibits protective and antitumorigenic activities through genomic and nongenomic signal transduction pathways. These results indicate that vitamin D deficiency results in an increase in the risk of developing ovarian cancer and that vitamin supplements may potentially be an efficient way of preventing cancer. Consequently, this review describes the epidemiology, molecular mechanism and evidence linking vitamin D deficiency to ovarian cancer.
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Affiliation(s)
- Hui Guo
- Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.,School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jing Guo
- Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.,School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Wenli Xie
- Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.,Shandong University, Jinan, Shandong, China
| | - Lingqin Yuan
- Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Xiugui Sheng
- Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong, China. .,Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, Guangdong, China.
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37
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Robertson J, Raizer J, Hodges JS, Gradishar W, Allen JA. Risk factors for the development of paclitaxel‐induced neuropathy in breast cancer patients. J Peripher Nerv Syst 2018; 23:129-133. [DOI: 10.1111/jns.12271] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 04/20/2018] [Accepted: 04/22/2018] [Indexed: 12/14/2022]
Affiliation(s)
- Jetter Robertson
- Department of Neurology University of Minnesota Minneapolis Minnesota
| | - Jeffrey Raizer
- Department of Neurology Northwestern University Chicago Illinois
| | - James S. Hodges
- Division of Biostatistics University of Minnesota Minneapolis Minnesota
| | | | - Jeffrey A. Allen
- Department of Neurology University of Minnesota Minneapolis Minnesota
- Department of Neurology Northwestern University Chicago Illinois
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38
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Kang J, Lee SH, Son JH, Lee JW, Choi YH, Choi JH, Paik WH, Ryu JK, Kim YT. Body mass index and weight change during initial period of chemotherapy affect survival outcome in advanced biliary tract cancer patients. PLoS One 2018; 13:e0195118. [PMID: 29608578 PMCID: PMC5880377 DOI: 10.1371/journal.pone.0195118] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 03/17/2018] [Indexed: 01/10/2023] Open
Abstract
Background The impact of obesity on survival is known to vary in different cancers. Advanced biliary tract cancer was rarely analyzed about the relationship between obesity and prognosis. We performed this study to evaluate the BMI and body weight change as prognostic factors for advanced biliary tract cancer patients with palliative chemotherapy. Methods Between January 2005 and December 2016, two hundred and seventy-six patients who underwent chemotherapy for biliary tract cancer were retrospectively analyzed. The relationship between BMI (kg/m2) and clinical outcomes including overall and progression-free survival was assessed. Additionally the relationship between change in body composition and overall survival was evaluated. Results Median overall survival was 9.7 months for underweight patients, 10.1 months for normal patients, 15.8 months for overweight group, 13.1 months for obese patients, respectively. (p = 0.047) Univariate analysis showed that BMI, stage III, age less than 64 year-old, gallbladder cancer, operation, radiotherapy and ECOG performance were significantly associated with better survival. Compared with normal patients, overweight patients (BMI 23–24.9kg/m2) had a reduced risk of mortality in multivariate analysis (HR 0.632; 95% CI 0.436–0.918, p = 0.016). In the additional analysis for the effect of changes in body weight and BMI to the overall survival, decrease in body weight and BMI (HR 1.410, 95% CI 1.168–1.986, p = 0.046) was associated with a shorter in overall survival. Conclusion Overweight status and the maintenance of body weight during the initial period of chemotherapy are important and independent predictors of better overall survival in advanced biliary tract cancer patients.
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Affiliation(s)
- Jinwoo Kang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Gastroenterolgy and Hepatology, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Sang Hyub Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- * E-mail:
| | - Jun Hyuk Son
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
| | - Jae Woo Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Mediplex Sejong Hospital, Gyeyang-gu, Incheon, Korea
| | - Young Hoon Choi
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Jin Ho Choi
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Woo Hyun Paik
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Ji Kon Ryu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Yong-Tae Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
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Vincenzi B, Badalamenti G, Armento G, Silletta M, Spalato Ceruso M, Catania G, Napolitano A, Maltese G, Valeri S, Incorvaia L, Santini D, Tonini G. Body Mass Index as a Risk Factor for Toxicities in Patients with Advanced Soft-Tissue Sarcoma Treated with Trabectedin. Oncology 2018; 95:1-7. [PMID: 29510410 DOI: 10.1159/000487266] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 10/26/2017] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS. METHODS Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on ≥1 anthracycline ± ifosfamide regimen were retrospectively reviewed. RESULTS Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups. CONCLUSIONS The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin.
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Affiliation(s)
- Bruno Vincenzi
- Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy
| | - Giuseppe Badalamenti
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Grazia Armento
- Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy
| | | | | | - Giovanna Catania
- Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy.,Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | | | | | - Sergio Valeri
- Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy
| | - Lorena Incorvaia
- Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy
| | - Daniele Santini
- Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy
| | - Giuseppe Tonini
- Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy
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40
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Myers CE, Hoelzinger DB, Truong TN, Chew LA, Myles A, Chaudhuri L, Egan JB, Liu J, Gendler SJ, Cohen PA. Chemotherapy can induce weight normalization of morbidly obese mice despite undiminished ingestion of high fat diet. Oncotarget 2018; 8:5426-5438. [PMID: 28076839 PMCID: PMC5354920 DOI: 10.18632/oncotarget.14576] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 12/05/2016] [Indexed: 02/06/2023] Open
Abstract
Morbidly obese patients who accomplish substantial weight loss often display a long-term decline in their resting metabolism, causing even relatively restrained caloric intake to trigger a relapse to the obese state. Paradoxically, we observed that morbidly obese mice receiving chemotherapy for cancer experienced spontaneous weight reduction despite unabated ingestion of their high fat diet (HFD). This response to chemotherapy could also be achieved in morbidly obese mice without cancer. Optimally dosed methotrexate (MTX) or cyclophosphamide (CY) enabled the mice to completely and safely normalize their body weight despite continued consumption of obesogenic quantities of HFD. Weight reduction was not attributable to decreased HFD intake, enhanced energy expenditure or malabsorption. MTX or CY dosing significantly depleted both adipose tissue and preadipocyte progenitors. Remarkably, however, despite continued high fat feeding, a compensatory increase in hepatocyte lipid storage was not observed, but rather the opposite. Gene microarray liver analyses demonstrated that HFD mice receiving MTX or CY experienced significantly inhibited lipogenesis and lipid storage, whereas Enho (energy homeostasis) gene expression was significantly upregulated. Further metabolic studies employing a human hepatocellular line revealed that MTX treatment preserved robust oxidative phosphorylation, but also promoted mitochondrial uncoupling with a surge in proton leak. This is the first report that certain optimally dosed chemotherapeutic agents can induce weight loss in morbidly obese mice without reduced dietary intake, apparently by depleting stores of adipocytes and their progenitors, curtailment of lipogenesis, and inconspicuous disposal of incoming dietary lipid via a steady state partial uncoupling of mitochondrial oxidative phosphorylation.
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Affiliation(s)
- Cheryl E Myers
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA
| | | | - Tiffany N Truong
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA
| | - Lindsey A Chew
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA
| | - Arpita Myles
- Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA
| | | | - Jan B Egan
- Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, USA
| | - Jun Liu
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA
| | - Sandra J Gendler
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA.,Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA.,Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
| | - Peter A Cohen
- Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA.,Department of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA
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41
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Mentoor I, Engelbrecht AM, van Jaarsveld PJ, Nell T. Chemoresistance: Intricate Interplay Between Breast Tumor Cells and Adipocytes in the Tumor Microenvironment. Front Endocrinol (Lausanne) 2018; 9:758. [PMID: 30619088 PMCID: PMC6297254 DOI: 10.3389/fendo.2018.00758] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 11/29/2018] [Indexed: 12/24/2022] Open
Abstract
Excess adipose tissue is a hallmark of an overweight and/or obese state as well as a primary risk factor for breast cancer development and progression. In an overweight/obese state adipose tissue becomes dysfunctional due to rapid hypertrophy, hyperplasia, and immune cell infiltration which is associated with sustained low-grade inflammation originating from dysfunctional adipokine synthesis. Evidence also supports the role of excess adipose tissue (overweight/obesity) as a casual factor for the development of chemotherapeutic drug resistance. Obesity-mediated effects/modifications may contribute to chemotherapeutic drug resistance by altering drug pharmacokinetics, inducing chronic inflammation, as well as altering tumor-associated adipocyte adipokine secretion. Adipocytes in the breast tumor microenvironment enhance breast tumor cell survival and decrease the efficacy of chemotherapeutic agents, resulting in chemotherapeutic resistance. A well-know chemotherapeutic agent, doxorubicin, has shown to negatively impact adipose tissue homeostasis, affecting adipose tissue/adipocyte functionality and storage. Here, it is implied that doxorubicin disrupts adipose tissue homeostasis affecting the functionality of adipose tissue/adipocytes. Although evidence on the effects of doxorubicin on adipose tissue/adipocytes under obesogenic conditions are lacking, this narrative review explores the potential role of obesity in breast cancer progression and treatment resistance with inflammation as an underlying mechanism.
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Affiliation(s)
- Ilze Mentoor
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
| | - Paul J. van Jaarsveld
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town, South Africa
- Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Theo Nell
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa
- *Correspondence: Theo Nell
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Cuello MA, Kato S, Liberona F. The impact on high-grade serous ovarian cancer of obesity and lipid metabolism-related gene expression patterns: the underestimated driving force affecting prognosis. J Cell Mol Med 2017; 22:1805-1815. [PMID: 29266765 PMCID: PMC5824367 DOI: 10.1111/jcmm.13463] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 10/21/2017] [Indexed: 01/06/2023] Open
Abstract
To investigate whether specific obesity/metabolism‐related gene expression patterns affect the survival of patients with ovarian cancer. Clinical and genomic data of 590 samples from the high‐grade ovarian serous carcinoma (HGOSC) study of The Cancer Genome Atlas (TCGA) and 91 samples from the Australian Ovarian Cancer Study were downloaded from the International Cancer Genome Consortium (ICGC) portal. Clustering of mRNA microarray and reverse‐phase protein array (RPPA) data was performed with 83 consensus driver genes and 144 obesity and lipid metabolism‐related genes. Association between different clusters and survival was analyzed with the Kaplan–Meier method and a Cox regression. Mutually exclusive, co‐occurrence and network analyses were also carried out. Using RNA and RPPA data, it was possible to identify two subsets of HGOSCs with similar clinical characteristics and cancer driver mutation profiles (e.g. TP53), but with different outcome. These differences depend more on up‐regulation of specific obesity and lipid metabolism‐related genes than on the number of gene mutations or copy number alterations. It was also found that CD36 and TGF‐ß are highly up‐regulated at the protein levels in the cluster with the poorer outcome. In contrast, BSCL2 is highly up‐regulated in the cluster with better progression‐free and overall survival. Different obesity/metabolism‐related gene expression patterns constitute a risk factor for prognosis independent of the therapy results in the Cox regression. Prognoses were conditioned by the differential expression of obesity and lipid metabolism‐related genes in HGOSCs with similar cancer driver mutation profiles, independent of the initial therapeutic response.
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Affiliation(s)
- Mauricio A Cuello
- Division of Obstetrics and Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sumie Kato
- Division of Obstetrics and Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisca Liberona
- Division of Obstetrics and Gynecology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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Lee YC, Lheureux S, Oza AM. Treatment strategies for endometrial cancer: current practice and perspective. Curr Opin Obstet Gynecol 2017; 29:47-58. [PMID: 27941361 DOI: 10.1097/gco.0000000000000338] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Endometrial cancer incidence is increasing in North America and is a major cause of morbidity and mortality in women. We review recent literature published on treatment of endometrial cancer and highlight areas of active interest. RECENT FINDINGS There has been movement toward minimal invasive surgery at diagnosis; lymph node staging remains controversial and continues to be investigated. Progress has been made to establish consensus on endometrial cancer risk classification to promote consistency for future trial design. Molecular characterization of endometrial cancer and its integration into clinicopathological profiling to develop predictive biomarkers for treatment selection are active areas of research. Optimal adjuvant treatment strategy in high-risk endometrial cancer remains to be defined with recognition of treatment-related toxicity. Despite encouraging results in drug development for treatment of advanced/recurrent endometrial cancer, no targeted therapies beyond hormonal therapy are approved. There is an urgent need for scientifically validated therapy with predictive biomarkers. SUMMARY Our understanding of endometrial cancer has evolved through improvements in molecular biology, allowing improved definition of target-specific therapies. The precise role and sequence of conventional and targeted therapies, including immunotherapy, will require careful attention to the design of clinical trials with translational emphasis to allow the discovery, validation, and implementation of predictive biomarkers into clinical care.
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Affiliation(s)
- Yeh C Lee
- Drug Development Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
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Radiation-related toxicities and outcomes in endometrial cancer: are obese women at a disadvantage? Int J Clin Oncol 2017. [PMID: 28620815 DOI: 10.1007/s10147-017-1147-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To assess the impact of body mass index (BMI) on radiotherapy toxicities in endometrial cancer patients. METHODS This was a retrospective cohort study of women diagnosed with endometrial cancer between January 2006 and December 2014 at the Royal Cornwall Hospital Trust. Women who received radiotherapy as part of their treatment, including external beam radiotherapy (EBRT) and/or vaginal brachytherapy were included. Radiation-related toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) guidelines. Toxicity outcomes were compared across BMI groups-non-obese (BMI <30 kg/m2) and obese (BMI ≥30 kg/m2)-according to radiotherapy treatment received (EBRT, brachytherapy or a combination). RESULTS Of a total of 159 women who received radiotherapy, 110 were eligible for inclusion in the study. Sixty-three women had a BMI <30 kg/m2 and 47 women were obese. Obese women had poorer Eastern Cooperative Oncology Group performance status (P = 0.021) and more comorbidities (P < 0.001) compared to the non-obese group. Total (any) toxicity rates were 60.3, 72.7 and 52.0% for EBRT and brachytherapy (N = 63), single-mode EBRT (N = 22) and brachytherapy (N = 25), respectively. BMI was not associated with the incidence of acute and late radiation toxicities in the different radiotherapy groups, and there were no differences in individual complications between the BMI groups. CONCLUSION When comparing obese to non-obese women, obesity does not negatively impact the incidence of radiation toxicities in endometrial cancer. However, toxicities remain an important challenge as they are common and negatively influence the quality of life (QoL) of survivors. Future studies need to further explore the role of BMI and possible interventions to improve toxicities and QoL.
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Abstract
Measures of body weight and anthropometrics such as body mass index (BMI) are commonly used to assess nutritional status in clinical conditions including cancer. Extensive research has evaluated associations between body weight and prognosis in ovarian cancer patients, yet little is known about the potential impact of body composition (fat mass (FM) and fat-free mass (FFM)) in these patients. Thus, the purpose of this publication was to review the literature (using PubMed and EMBASE) evaluating the impact of body weight and particularly body composition on surgical complications, morbidity, chemotherapy dosing and toxicity (as predictors of prognosis), and survival in ovarian cancer patients. Body weight is rarely associated with intra-operative complications, but obesity predicts higher rates of venous thromboembolism and wound complications post-operatively in ovarian cancer patients. Low levels of FM and FFM are superior predictors of length of hospital stay compared to measures of body weight alone, but the role of body composition on other surgical morbidities is unknown. Obesity complicates chemotherapy dosing due to altered pharmacokinetics, imprecise dosing strategies, and wide variability in FM and FFM. Measurement of body composition has the potential to reduce toxicity if the results are incorporated into chemotherapy dosing calculations. Some findings suggest that excess body weight adversely affects survival, while others find no such association. Limited studies indicate that FM is a better predictor of survival than body weight in ovarian cancer patients, but the direction of this relationship has not been determined. In conclusion, body composition as an indicator of nutritional status is a better prognostic tool than body weight or BMI alone in ovarian cancer patients.
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Furlanetto J, Eiermann W, Marmé F, Reimer T, Reinisch M, Schmatloch S, Stickeler E, Thomssen C, Untch M, Denkert C, von Minckwitz G, Lederer B, Nekljudova V, Weber K, Loibl S, Möbus V. Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study. Ann Oncol 2016; 27:2053-2059. [DOI: 10.1093/annonc/mdw315] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 07/28/2016] [Indexed: 12/14/2022] Open
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Craig ER, Londoño AI, Norian LA, Arend RC. Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review. Gynecol Oncol 2016; 143:674-683. [PMID: 27751590 DOI: 10.1016/j.ygyno.2016.10.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/26/2016] [Accepted: 10/03/2016] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Epithelial ovarian cancer continues to be the deadliest gynecologic malignancy. Patients with both diabetes mellitus and obesity have poorer outcomes, yet research correlating metabolic abnormalities, such as metabolic syndrome, to ovarian cancer risk and outcomes is lacking. This article reviews the literature regarding metabolic derangements and their relationship to epithelial ovarian cancer, with a focus on potential mechanisms behind these associations. METHODS PubMed and Google Scholar were searched for articles in the English language regarding epithelial ovarian cancer, obesity, diabetes mellitus, and metabolic syndrome, with a focus on studies conducted since 1990. RESULTS Obesity, type II diabetes mellitus, and metabolic syndrome have been associated with poor outcomes in epithelial ovarian cancer. More studies investigating the relationship between metabolic syndrome and epithelial ovarian cancer are needed. A variety of pathologic factors may contribute to cancer risk in patients with metabolic derangements, including altered adipokine and cytokine expression, altered immune responses to tumor cells, and changes in pro-tumorigenic signaling pathways. CONCLUSION More research is needed to examine the effects of metabolic syndrome on epithelial ovarian cancer risk and mortality, as well as the underlying pathophysiologies in patients with obesity, diabetes mellitus, and metabolic syndrome that may be targeted for therapeutic intervention.
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Affiliation(s)
- Eric R Craig
- School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Angelina I Londoño
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lyse A Norian
- Department of Nutrition Sciences and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rebecca C Arend
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA.
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McAlpine JN, Temkin SM, Mackay HJ. Endometrial cancer: Not your grandmother's cancer. Cancer 2016; 122:2787-98. [DOI: 10.1002/cncr.30094] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 03/11/2016] [Accepted: 03/15/2016] [Indexed: 12/20/2022]
Affiliation(s)
- Jessica N. McAlpine
- Department of Gynecology and Obstetrics, Division Gynecologic Oncology; University of British Columbia and British Columbia Cancer Agency; Vancouver British Columbia Canada
| | - Sarah M. Temkin
- Kelly Gynecologic Oncology Service, Johns Hopkins School of Medicine; Baltimore Maryland
| | - Helen J. Mackay
- Division of Medical Oncology and Hematology, Faculty of Medicine; University of Toronto, Sunnybrook Odette Cancer Center; Toronto Ontario Canada
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Investigating the Impact of Body Mass Index on Intraperitoneal Chemotherapy Outcomes in Ovarian and Fallopian Tube Cancer. Int J Gynecol Cancer 2016; 26:1033-40. [PMID: 27206282 DOI: 10.1097/igc.0000000000000729] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVES The aim of this study was to investigate the impact of body mass index (BMI) on completion, complications, and clinical outcomes of intraperitoneal (IP) chemotherapy in patients with advanced-stage ovarian cancer. METHODS Patients with optimally cytoreduced International Federation of Gynecology and Obstetrics stage IIIC ovarian cancer treated with IP chemotherapy were retrospectively identified using an institutional review board-approved database. Clinical data were abstracted from the longitudinal medical record. Survival estimates were calculated using the Kaplan-Meier method. RESULTS Ninety-two patients (35.5%) completed at least one cycle of IP chemotherapy. For these patients, there was no difference in histology, surgical complexity, or degree of cytoreduction based on BMI. Sixty-five percent of normal weight, 70% of overweight, and 59.1% of obese women completed 6 cycles (P = 0.697). There was also no significant difference in IP chemotherapy complications (P = 0.303). Body mass index had no impact on disease-free survival (P = 0.44) or overall survival, with a median overall survival of 68.5 months for normal weight, 65.9 months for overweight, and 61.7 months for obese women (P = 0.25). However, on multivariate analysis, obesity had an odds ratio of 2.92 (P = 0.02) for mortality. There was a trend toward treatment with intravenous chemotherapy (84.2%) over IP (15.8%) in patients with class II obesity (P = 0.06). DISCUSSION There was no difference in completion of IP chemotherapy or complications with respect to BMI; however, there was a trend away from treatment with IP therapy in extreme obesity. These data suggest that IP chemotherapy is feasible in obese patients without incurring increased morbidity.
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Matsuo K, Moeini A, Cahoon SS, Machida H, Ciccone MA, Grubbs BH, Muderspach LI. Weight Change Pattern and Survival Outcome of Women with Endometrial Cancer. Ann Surg Oncol 2016; 23:2988-97. [PMID: 27112587 DOI: 10.1245/s10434-016-5237-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The aim of this study was to determine the association between weight change patterns and survival outcomes of women with endometrial cancer. METHODS This retrospective study examined surgically-staged endometrial cancer cases with available weight information between 1999 and 2013 (n = 665). Proportional body mass index (delta-BMI) change at 6 months, 1 and 2 years after hysterectomy was compared with baseline BMI and correlated to patient demographics, tumor characteristics, treatment type, and disease-free survival (DFS) and overall survival (OS). RESULTS Mean BMI was 35.6, and 69 % of cases were obese. At 6 months, 1 and 2 years after surgery, 39.1, 51.6, and 57.0 % of the study population, respectively, gained weight compared with pre-treatment baseline. In univariate analysis, 6-month delta-BMI change was significantly associated with DFS and OS, demonstrating bidirectional effects (both p < 0.001): 5-year rates, ≥15.0 % delta-BMI loss (33.5 and 59.1 %), 7.5-14.9 % loss (67.3 and 70.0 %), <7.5 % loss (87.8 and 95.7 %), <7.5 % gain (87.2 and 90.3 %), 7.5-14.9 % gain (64.6 and 67.6 %), and ≥15.0 % gain (32.5 and 66.7 %). In multivariable analysis controlling for age, ethnicity, baseline BMI, histology, grade, stage, chemotherapy, and radiotherapy, 6-month delta-BMI change remained an independent prognostic factor for DFS and OS (all p < 0.05): adjusted hazard ratios, ≥15 % delta-BMI loss (3.35 and 5.39), 7.5-14.9 % loss (2.35 and 4.19), 7.5-14.9 % gain (2.58 and 3.33), and ≥15.0 % gain (2.50 and 3.45) compared with <7.5 % loss. Similar findings were observed at a 1-year time point (p < 0.05). Baseline BMI was not associated with survival outcome (p > 0.05). CONCLUSION Our results demonstrated that endometrial cancer patients continued to gain weight after hysterectomy, and post-treatment weight change had bidirectional effects on survival outcome.
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Affiliation(s)
- Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, 90033, USA. .,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
| | - Aida Moeini
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Sigita S Cahoon
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Hiroko Machida
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Marcia A Ciccone
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, 90033, USA
| | - Brendan H Grubbs
- Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, USA
| | - Laila I Muderspach
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, Los Angeles, CA, 90033, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
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