J Cancer Res Clin Oncol (2014) 140:681–683 DOI 10.1007/s00432-014-1609-3
Letter to the Editor
Arginine‑supplemented enteral nutrition Jutta Huebner · Ralph Muecke
Received: 1 February 2014 / Accepted: 3 February 2014 / Published online: 13 February 2014 © Springer-Verlag Berlin Heidelberg 2014
We have read with interest the paper published in your journal by Zhao et al. (2013). The authors describe a double-blinded RCT with patients undergoing gastrectomy for gastric cancer. The trial group was given an arginine-enriched enteral tube feeding, while the control group was given a standard diet. The authors report a significant improvement in overall survival of these patients. The data are astonishing and if correct would have an impact on medical care for this group of patients. Before changing practice skepticism is mandatory. The study has some limitations (single-center study, only 73 patients, no stratification according to final histology). Moreover, the dosage the authors chose is low. De Luis et al. (2010) published one of the rare studies which tested two doses of arginine 12.3 g per day (“medium dose”) and 20 g per day (“high dose”). Nevertheless, the study provides some facts which add to our knowledge on nutrition in oncology and they challenge our attitude toward nutrition in oncology as a less important discipline.
What is the scientific context of the work of Zhao and colleagues? Arginine is given as part of “immunonutrition,” and most data stem from studies conducted in the post-or perioperative setting. Most of these studies have provided positive data concerning postoperative complications especially regarding infections (e.g., Farreras et al. 2005; de Luis et al. 2005; Nakamura et al. 2005; Casas-Rodera et al. 2008; Okamoto et al. 2009; Felekis et al. 2010; de Luis et al. 2013; Turnock et al. 2013). Other authors were not able to verify these data (e.g., Helminen et al. 2007). Therefore, the authors of a review in 2012 concluded that data are contradictory and that careful planning of further studies is mandatory (Casas Rodera et al. 2012). Yet, the guideline of the European Society for Clinical Nutrition and Metabolism (ESPEN) on enteral nutrition recommends to “use preoperative enteral nutrition preferably with immune-modulating substrates (arginine, o-3 fatty acids, nucleotides) for 7 days in all patients undergoing major abdominal surgery independent of their nutritional status” (Arends et al. 2006).
Role of arginine J. Huebner (*) Dr. Senckenbergisch Chronomedical Institute, J.W. Goethe University, Theodor‑Stern‑Kai 7, 60590 Frankfurt am Main, Germany e-mail: [email protected]‑frankfurt.de R. Muecke Department of Radiotherapy and Radiation Oncology, Ruhr University, Bochum, Germany
Arginine is an amino acid necessary for growth and wound healing. It has several immunomodulatory effects. The discussion is open as to whether arginine by its immuneenhancing effect also modifies cancer cachexia (Popovic et al. 2007; Buijs et al. 2012). Only few studies have been published which tested arginine as a single agent. In patients with head and neck cancer, arginine-enriched formula diet reduced
13
682
postoperative fistula but had no effect on infections. Length of stay at hospital was decreased (de Luis et al. 2007, 2009).
Safety concerns regarding arginine On the other hand, arginine also stimulates growth hormone, insulin-like growth factor 1 and insulin and thus could also enhance tumor growth and angiogenesis (Lind 2004; Yeatman et al. 1991). In 1992, Park and colleagues could demonstrate that arginine given orally before operation enhances protein synthesis and KI 67 in breast cancer tissue (Park et al. 1992). A case series describes treatment of hepatocellular cancer by deprivation of arginine (Cheng et al. 2005). According to these contradictory data, Bossola et al. (2011) in a systematic review resume that “it remains unknown if PN or EN enriched with specific nutrients such as arginine, omega-3 fatty acids, and glutamine can affect tumor growth in humans.”
Do we have clinical data which support the authors results? In fact, only few clinical data so far support the data from Zhao and colleagues. In 1998, Heys and colleagues published data on potentiation of the response to chemotherapy in patients with breast cancer (Heys et al. 1998). To our knowledge, the only clinical trial on arginine reporting on survival is the study by Buijs and colleagues (2010). In this study, the authors report a significantly better overall survival in the group receiving arginine-enriched nutrition. Furthermore, two other articles with quite different approaches have shown that interventions besides classical treatment options can help to improve survival. Well known are the data from Temel et al. (2010) who have shown that early palliative care has a decisive effect on survival in lung cancer patients. So far it is not quite clear how this intervention worked. Yet, the data are accepted in the scientific community. Less known is the trial by Troeger et al. (2013) who report a significant improvement of overall survival in patients with pancreatic cancer given mistletoe thrice weekly in a primary care center in comparison with no treatment. While these authors claim mistletoe being the active agent, in accordance with Temel, care more probably has been the decisive element of this treatment which also was able to reduce weight loss. Several studies have shown that weight loss is associated with worse prognosis in cancer patients.
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J Cancer Res Clin Oncol (2014) 140:681–683
What can we learn from the article by Zhao and colleagues? In most other clinical trials on post- or perioperative nutrition, a mixture of omega-3-fatty acids, RNA and arginine (sometimes combined with other amino acids as glutamine) has been used. As a consequence, we were not able to distinguish which substance(s) is (are) decisive and whether there are even counterproductive agents in the mixture. (For glutamine, e.g., there are some doubts on safety as it might enhance tumor growth and a systematic review on patients with stem cell transplantation summarizes that glutamine may reduce mucositis but that overall survival also seems to be reduced (Crowther et al. 2009).) By choosing overall survival as the primary endpoint, the authors planned a most ambitious project which in one setting would be able to deal with questions of efficacy as well as safety concerns. More important is the fact that this study points to a topic in oncology which often is disregarded. So far only few studies focused on nutrition and it is considered a more or less supportive means. Perhaps the attention of oncologists will rise if more studies provide positive data on survival of cancer patients by nutritional interventions. Conflict of interest The authors declare no conflicts of interest.
References Arends J, Bodoky G, Bozzetti F, Fearon K, Muscaritoli M, Selga G, van Bokhorst-de van der Schueren MAE, von Meyenfeldt M, Zuercher G, Fietkau G, Aulbert E, Frick B, Holm M, Kneba M, Mestrom HJ, Zander A (2006) ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutrit 25:245–259 Bossola M, Pacelli F, Rosa F, Tortorelli A, Doglietto GB (2011) Does nutrition support stimulate tumor growth in humans? Nutr Clin Pract 26(2):174–180 Buijs N, Luttikhold J, Houdijk AP, van Leeuwen PA (2012) The role of a disturbed arginine/NO metabolism in the onset of cancer cachexia: a working hypothesis. Curr Med Chem 19(31):5278–5286 Casas-Rodera P, Gómez-Candela C, Benítez S, Mateo R, Armero M, Castillo R, Culebras JM (2008) Immunoenhanced enteral nutrition formulas in head and neck cancer surgery: a prospective, randomized clinical trial. Nutr Hosp 23(2):105–110 Casas Rodera P, de Luis DA, Gómez Candela C, Culebras JM (2012) Immunoenhanced enteral nutrition formulas in head and neck cancer surgery: a systematic review. Nutr Hosp 27(3):681–690 Cheng PN, Leung YC, Lo WH, Tsui SM, Lam KC (2005) Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: arginase as a potential drug candidate for hepatocellular carcinoma. Cancer Lett 224(1):67–80 Crowther M, Avenell A, Culligan DJ (2009) Systematic review and meta-analyses of studies of glutamine supplementation in haematopoietic stem cell transplantation. Bone Marrow Transpl 44(7):413–425
J Cancer Res Clin Oncol (2014) 140:681–683 De Luis DA, Arranz M, Aller R, Izaola O, Cuellar L, Terroba MC (2005) Immunoenhanced enteral nutrition, effect on inflammatory markers in head and neck cancer patients. Eur J Clin Nutr 59(1):145–147 De Luis DA, Izaola O, Cuellar L, Terroba MC, Martin T, Aller R (2007) Clinical and biochemical outcomes after a randomized trial with a high dose of enteral arginine formula in postsurgical head and neck cancer patients. Eur J Clin Nutr 61(2):200–204 De Luis DA, Izaola O, Cuellar L, Terroba MC, Martin T, Aller R (2009) High dose of arginine enhanced enteral nutrition in postsurgical head and neck cancer patients. A randomized clinical trial. Eur Rev Med Pharmacol Sci 13(4):279–283 De Luis DA, Izaola O, Cuellar L, Terroba MC, Martin T, Ventosa M (2010) A randomized double-blind clinical trial with two different doses of arginine enhanced enteral nutrition in postsurgical cancer patients. Eur Rev Med Pharmacol Sci 14(11):941–945 De Luis DA, Izaola O, Cuellar L, Terroba MC, de la Fuente B, Cabezas G (2013) A randomized clinical trial with two doses of a omega 3 fatty acids oral and arginine enhanced formula in clinical and biochemical parameters of head and neck cancer ambulatory patients. Eur Rev Med Pharmacol Sci 17(8):1090–1094 Farreras N, Artigas V, Cardona D, Rius X, Trias M, González JA (2005) Effect of early postoperative enteral immunonutrition on wound healing in patients undergoing surgery for gastric cancer. Clin Nutr 24(1):55–65 Felekis D, Eleftheriadou A, Papadakos G, Bosinakou I, Ferekidou E, Kandiloros D, Katsaragakis S, Charalabopoulos K, Manolopoulos L (2010) Effect of perioperative immuno-enhanced enteral nutrition on inflammatory response, nutritional status, and outcomes in head and neck cancer patients undergoing major surgery. Nutr Cancer 62(8):1105–1112 Helminen H, Raitanen M, Kellosalo J (2007) Immunonutrition in elective gastrointestinal surgery patients. Scand J Surg 96(1):46–50 Heys SD, Ogston K, Miller I, Hutcheon AW, Walker LG, Sarker TK, Dewar J, Ah-See AK, Eremin O (1998) Potentiation of the response to chemotherapy in patients with breast cancer by dietary supplementation with l-arginine: results of a randomized controlled trial. Int J Oncol 12:221–225
683 Lind DS (2004) Arginine and cancer. J Nutr 134(10 Suppl):2837S–2841S Nakamura K, Kariyazono H, Komokata T, Hamada N, Sakata R, Yamada K (2005) Influence of preoperative administration of omega-3 fatty acid-enriched supplement on inflammatory and immune responses in patients undergoing major surgery for cancer. Nutrition 21(6):639–649 Okamoto Y, Okano K, Izuishi K, Usuki H, Wakabayashi H, Suzuki Y (2009) Attenuation of the systemic inflammatory response and infectious complications after gastrectomy with preoperative oral arginine and omega-3 fatty acids supplemented immunonutrition. World J Surg 33(9):1815–1821 Park KG, Heys SD, Blessing K, Kelly P, McNurlan MA, Eremin O, Garlick PJ (1992) Stimulation of human breast cancers by dietary arginine. Clin Sci 82:413–417 Popovic PJ, Zeh HJ III, Ochoa JB (2007) Arginine and immunity. J Nutr 137(6 Suppl 2):1681S–1686S Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ (2010) Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 362:733–742 Troeger W, Galun D, Reif M, Schumann A, Stankovic´ N, Milic´evic´ M (2013) Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer 49(18):3788–3797 Turnock A, Calder PC, West AL, Izzard M, Morton RP, Plank LD (2013) Perioperative immunonutrition in well-nourished patients undergoing surgery for head and neck cancer: evaluation of inflammatory and immunologic outcomes. Nutrients 5(4):1186–1199 Yeatman TJ, Risley GL, Brunson ME (1991) Depletion of dietary arginine inhibits growth of metastatic tumor. Arch Surg 126:1376–1381 Zhao H, Zhao H, Wang Y, Jing H, Ding Q, Xue J (2013) Randomized clinical trial of arginine-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing gastric cancer surgery. Cancer Res Clin Oncol 139(9):1465–1470
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Letter to the Editor
Arginine‑supplemented enteral nutrition Jutta Huebner · Ralph Muecke
Received: 1 February 2014 / Accepted: 3 February 2014 / Published online: 13 February 2014 © Springer-Verlag Berlin Heidelberg 2014
We have read with interest the paper published in your journal by Zhao et al. (2013). The authors describe a double-blinded RCT with patients undergoing gastrectomy for gastric cancer. The trial group was given an arginine-enriched enteral tube feeding, while the control group was given a standard diet. The authors report a significant improvement in overall survival of these patients. The data are astonishing and if correct would have an impact on medical care for this group of patients. Before changing practice skepticism is mandatory. The study has some limitations (single-center study, only 73 patients, no stratification according to final histology). Moreover, the dosage the authors chose is low. De Luis et al. (2010) published one of the rare studies which tested two doses of arginine 12.3 g per day (“medium dose”) and 20 g per day (“high dose”). Nevertheless, the study provides some facts which add to our knowledge on nutrition in oncology and they challenge our attitude toward nutrition in oncology as a less important discipline.
What is the scientific context of the work of Zhao and colleagues? Arginine is given as part of “immunonutrition,” and most data stem from studies conducted in the post-or perioperative setting. Most of these studies have provided positive data concerning postoperative complications especially regarding infections (e.g., Farreras et al. 2005; de Luis et al. 2005; Nakamura et al. 2005; Casas-Rodera et al. 2008; Okamoto et al. 2009; Felekis et al. 2010; de Luis et al. 2013; Turnock et al. 2013). Other authors were not able to verify these data (e.g., Helminen et al. 2007). Therefore, the authors of a review in 2012 concluded that data are contradictory and that careful planning of further studies is mandatory (Casas Rodera et al. 2012). Yet, the guideline of the European Society for Clinical Nutrition and Metabolism (ESPEN) on enteral nutrition recommends to “use preoperative enteral nutrition preferably with immune-modulating substrates (arginine, o-3 fatty acids, nucleotides) for 7 days in all patients undergoing major abdominal surgery independent of their nutritional status” (Arends et al. 2006).
Role of arginine J. Huebner (*) Dr. Senckenbergisch Chronomedical Institute, J.W. Goethe University, Theodor‑Stern‑Kai 7, 60590 Frankfurt am Main, Germany e-mail: [email protected]‑frankfurt.de R. Muecke Department of Radiotherapy and Radiation Oncology, Ruhr University, Bochum, Germany
Arginine is an amino acid necessary for growth and wound healing. It has several immunomodulatory effects. The discussion is open as to whether arginine by its immuneenhancing effect also modifies cancer cachexia (Popovic et al. 2007; Buijs et al. 2012). Only few studies have been published which tested arginine as a single agent. In patients with head and neck cancer, arginine-enriched formula diet reduced
13
682
postoperative fistula but had no effect on infections. Length of stay at hospital was decreased (de Luis et al. 2007, 2009).
Safety concerns regarding arginine On the other hand, arginine also stimulates growth hormone, insulin-like growth factor 1 and insulin and thus could also enhance tumor growth and angiogenesis (Lind 2004; Yeatman et al. 1991). In 1992, Park and colleagues could demonstrate that arginine given orally before operation enhances protein synthesis and KI 67 in breast cancer tissue (Park et al. 1992). A case series describes treatment of hepatocellular cancer by deprivation of arginine (Cheng et al. 2005). According to these contradictory data, Bossola et al. (2011) in a systematic review resume that “it remains unknown if PN or EN enriched with specific nutrients such as arginine, omega-3 fatty acids, and glutamine can affect tumor growth in humans.”
Do we have clinical data which support the authors results? In fact, only few clinical data so far support the data from Zhao and colleagues. In 1998, Heys and colleagues published data on potentiation of the response to chemotherapy in patients with breast cancer (Heys et al. 1998). To our knowledge, the only clinical trial on arginine reporting on survival is the study by Buijs and colleagues (2010). In this study, the authors report a significantly better overall survival in the group receiving arginine-enriched nutrition. Furthermore, two other articles with quite different approaches have shown that interventions besides classical treatment options can help to improve survival. Well known are the data from Temel et al. (2010) who have shown that early palliative care has a decisive effect on survival in lung cancer patients. So far it is not quite clear how this intervention worked. Yet, the data are accepted in the scientific community. Less known is the trial by Troeger et al. (2013) who report a significant improvement of overall survival in patients with pancreatic cancer given mistletoe thrice weekly in a primary care center in comparison with no treatment. While these authors claim mistletoe being the active agent, in accordance with Temel, care more probably has been the decisive element of this treatment which also was able to reduce weight loss. Several studies have shown that weight loss is associated with worse prognosis in cancer patients.
13
J Cancer Res Clin Oncol (2014) 140:681–683
What can we learn from the article by Zhao and colleagues? In most other clinical trials on post- or perioperative nutrition, a mixture of omega-3-fatty acids, RNA and arginine (sometimes combined with other amino acids as glutamine) has been used. As a consequence, we were not able to distinguish which substance(s) is (are) decisive and whether there are even counterproductive agents in the mixture. (For glutamine, e.g., there are some doubts on safety as it might enhance tumor growth and a systematic review on patients with stem cell transplantation summarizes that glutamine may reduce mucositis but that overall survival also seems to be reduced (Crowther et al. 2009).) By choosing overall survival as the primary endpoint, the authors planned a most ambitious project which in one setting would be able to deal with questions of efficacy as well as safety concerns. More important is the fact that this study points to a topic in oncology which often is disregarded. So far only few studies focused on nutrition and it is considered a more or less supportive means. Perhaps the attention of oncologists will rise if more studies provide positive data on survival of cancer patients by nutritional interventions. Conflict of interest The authors declare no conflicts of interest.
References Arends J, Bodoky G, Bozzetti F, Fearon K, Muscaritoli M, Selga G, van Bokhorst-de van der Schueren MAE, von Meyenfeldt M, Zuercher G, Fietkau G, Aulbert E, Frick B, Holm M, Kneba M, Mestrom HJ, Zander A (2006) ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutrit 25:245–259 Bossola M, Pacelli F, Rosa F, Tortorelli A, Doglietto GB (2011) Does nutrition support stimulate tumor growth in humans? Nutr Clin Pract 26(2):174–180 Buijs N, Luttikhold J, Houdijk AP, van Leeuwen PA (2012) The role of a disturbed arginine/NO metabolism in the onset of cancer cachexia: a working hypothesis. Curr Med Chem 19(31):5278–5286 Casas-Rodera P, Gómez-Candela C, Benítez S, Mateo R, Armero M, Castillo R, Culebras JM (2008) Immunoenhanced enteral nutrition formulas in head and neck cancer surgery: a prospective, randomized clinical trial. Nutr Hosp 23(2):105–110 Casas Rodera P, de Luis DA, Gómez Candela C, Culebras JM (2012) Immunoenhanced enteral nutrition formulas in head and neck cancer surgery: a systematic review. Nutr Hosp 27(3):681–690 Cheng PN, Leung YC, Lo WH, Tsui SM, Lam KC (2005) Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: arginase as a potential drug candidate for hepatocellular carcinoma. Cancer Lett 224(1):67–80 Crowther M, Avenell A, Culligan DJ (2009) Systematic review and meta-analyses of studies of glutamine supplementation in haematopoietic stem cell transplantation. Bone Marrow Transpl 44(7):413–425
J Cancer Res Clin Oncol (2014) 140:681–683 De Luis DA, Arranz M, Aller R, Izaola O, Cuellar L, Terroba MC (2005) Immunoenhanced enteral nutrition, effect on inflammatory markers in head and neck cancer patients. Eur J Clin Nutr 59(1):145–147 De Luis DA, Izaola O, Cuellar L, Terroba MC, Martin T, Aller R (2007) Clinical and biochemical outcomes after a randomized trial with a high dose of enteral arginine formula in postsurgical head and neck cancer patients. Eur J Clin Nutr 61(2):200–204 De Luis DA, Izaola O, Cuellar L, Terroba MC, Martin T, Aller R (2009) High dose of arginine enhanced enteral nutrition in postsurgical head and neck cancer patients. A randomized clinical trial. Eur Rev Med Pharmacol Sci 13(4):279–283 De Luis DA, Izaola O, Cuellar L, Terroba MC, Martin T, Ventosa M (2010) A randomized double-blind clinical trial with two different doses of arginine enhanced enteral nutrition in postsurgical cancer patients. Eur Rev Med Pharmacol Sci 14(11):941–945 De Luis DA, Izaola O, Cuellar L, Terroba MC, de la Fuente B, Cabezas G (2013) A randomized clinical trial with two doses of a omega 3 fatty acids oral and arginine enhanced formula in clinical and biochemical parameters of head and neck cancer ambulatory patients. Eur Rev Med Pharmacol Sci 17(8):1090–1094 Farreras N, Artigas V, Cardona D, Rius X, Trias M, González JA (2005) Effect of early postoperative enteral immunonutrition on wound healing in patients undergoing surgery for gastric cancer. Clin Nutr 24(1):55–65 Felekis D, Eleftheriadou A, Papadakos G, Bosinakou I, Ferekidou E, Kandiloros D, Katsaragakis S, Charalabopoulos K, Manolopoulos L (2010) Effect of perioperative immuno-enhanced enteral nutrition on inflammatory response, nutritional status, and outcomes in head and neck cancer patients undergoing major surgery. Nutr Cancer 62(8):1105–1112 Helminen H, Raitanen M, Kellosalo J (2007) Immunonutrition in elective gastrointestinal surgery patients. Scand J Surg 96(1):46–50 Heys SD, Ogston K, Miller I, Hutcheon AW, Walker LG, Sarker TK, Dewar J, Ah-See AK, Eremin O (1998) Potentiation of the response to chemotherapy in patients with breast cancer by dietary supplementation with l-arginine: results of a randomized controlled trial. Int J Oncol 12:221–225
683 Lind DS (2004) Arginine and cancer. J Nutr 134(10 Suppl):2837S–2841S Nakamura K, Kariyazono H, Komokata T, Hamada N, Sakata R, Yamada K (2005) Influence of preoperative administration of omega-3 fatty acid-enriched supplement on inflammatory and immune responses in patients undergoing major surgery for cancer. Nutrition 21(6):639–649 Okamoto Y, Okano K, Izuishi K, Usuki H, Wakabayashi H, Suzuki Y (2009) Attenuation of the systemic inflammatory response and infectious complications after gastrectomy with preoperative oral arginine and omega-3 fatty acids supplemented immunonutrition. World J Surg 33(9):1815–1821 Park KG, Heys SD, Blessing K, Kelly P, McNurlan MA, Eremin O, Garlick PJ (1992) Stimulation of human breast cancers by dietary arginine. Clin Sci 82:413–417 Popovic PJ, Zeh HJ III, Ochoa JB (2007) Arginine and immunity. J Nutr 137(6 Suppl 2):1681S–1686S Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ (2010) Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 362:733–742 Troeger W, Galun D, Reif M, Schumann A, Stankovic´ N, Milic´evic´ M (2013) Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer 49(18):3788–3797 Turnock A, Calder PC, West AL, Izzard M, Morton RP, Plank LD (2013) Perioperative immunonutrition in well-nourished patients undergoing surgery for head and neck cancer: evaluation of inflammatory and immunologic outcomes. Nutrients 5(4):1186–1199 Yeatman TJ, Risley GL, Brunson ME (1991) Depletion of dietary arginine inhibits growth of metastatic tumor. Arch Surg 126:1376–1381 Zhao H, Zhao H, Wang Y, Jing H, Ding Q, Xue J (2013) Randomized clinical trial of arginine-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing gastric cancer surgery. Cancer Res Clin Oncol 139(9):1465–1470
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