We would like to thank the writers for their interest in our work. We are happy to clarify some of the questions related to our earlier paper. Firstly, the writers make several points critiquing the VM-M3 model of metastatic cancer. We agree that there are limitations to the VM-M3 model, as is true for all research models; however, there are several reasons why we chose to utilize the VM-M3 model and consider it to be a good model of metastatic cancer.

1. The writers say that the VM-M3 model lacks external validation. In research, investigators often design new model systems to use in their work. This is how new research models come into being. Once established and published on, those models then begin to be used by other investigators. Dr. Seyfried developed the VM-M3 model at Boston College. Later, he shared the model with the D’Agostino lab to use in their studies at the University of South Florida. This model system is novel, and therefore is still undergoing testing, but it has been published on several times in multiple peer reviewed journals, and the model is currently being studied at other institutions in the US and abroad. This is a commonplace method in pre-clinical research. External validation is only accomplished after numerous separate labs have used the same experimental model over a number of years. It’s only through historical perspective that we can truly say a model has been validated, a process that has been ongoing for the VM-M3 model for many years now, but since it is relatively new (sadly research moves at a slow pace), the model is still working towards full external validation.

2. The writers critique the paper in a way that suggests they believe the model is intended to serve as a model for primary glioblastoma multiforme (GBM) brain cancer. However, this is a misinterpretation of the study. The model system in use is one for metastatic cancer because the cells are inherently highly metastatic, are derived from a spontaneously-formed tumor, are allowed to grow and spread naturally from the site of inoculation, and metastasize systemically throughout the body [1]. There is a severe lack of adequate metastatic cancer models, which is one reason why the VM-M3 model was developed. Most research on metastatic cancer involves injection of cancer cells into the tail vein of rodents, which then form tumors in various tissues; however, this technique fails to replicate the first half of the metastatic process which includes escape from the primary site of origin. Other models utilize carcinogen or transgene-induced tumors which have a variable time to tumor onset, size, and location, and aggressiveness of tumors, and they often metastasize with a highly variable consistency and speed, all introducing significant variability into the data [2]. These studies are thus often lengthy and costly which may explain deterred use and limited data on these models [3]. The VM-M3 model is a highly aggressive, consistent, and rapid model which provides several benefits as a model of metastatic cancer, including a similar response to chemotherapy as seen in humans with metastatic disease [4]. It is important that studies are performed on a variety of model types, while understanding their deficiencies, to provide our best understanding and the opportunity to replicate and study the metastatic process. The VM-M3 model is another tool in this tool box which provides many specific advantages.

3. The writers critique the use of GBM cells in this metastatic model because metastasis from primary GBM is considered rare clinically. As referenced in the paper, there are indeed numerous clinical reports documenting extraneural metastasis from GBM [5-12]. Still, extraneural GBM metastasis is a relatively rare phenomenon, which is likely due in large part to two primary reasons: 1) GBM is a devastating disease which typically causes death within 12-15 months, even with aggressive treatment. Metastasis is a phenomenon that typically occurs later in disease progression for most cancers. It is likely that most often, patients succumb to the primary tumor before metastatic disease has occurred or is clinically visible. 2) When a patient is suffering from a known GBM, it is not common to scan the rest of the body to look for metastatic disease because the GBM is the primary concern. When a patient dies from a GBM, other tissues are not typically examined for metastatic disease. The writers appear to have misinterpreted the intention of the section of the manuscript which references extraneural metastasis of GBM. These statements were included to demonstrate that GBMs are indeed capable of metastasizing systemically (which is clear in the medical literature) – not to say that GBMs do this commonly.

4. The writers critique the site of inoculation of the cancer cells. While the VM-M3 cells will sometimes metastasize systemically from the intracranial implantation site [13], in order to create a reliable rapid model of systemic metastasis, the VM-M3 cells are implanted in the subcutaneous fat pad, and the cells spread naturally from that location [1]. As previously mentioned, this is an improvement over one of the most popular methods of modeling metastasis – the tail vein injection method, since it also recapitulates invasion and intravasation into the circulation, not just the establishment of tumors in a distal location. Of course, it should also be acknowledged that ectopic implantation of cancer cells is a method that is widely accepted and utilized in cancer research, despite its obvious limitations. If the writers misunderstood that this paper is not meant to model primary GBM, it may explain the confusion, as of course intracranial implantation would be a preferred site to model primary GBM.

5. The writers critique that the VM-M3 model uses a background strain of inbred mice since they “lack the genetic heterogeneity of human patients.” This is an odd statement, as indeed, most rodent models in research use inbred background strains, and it is the lack of genetic heterogeneity of the host that is the reason for using them. It allows researchers to control for these variables in their study, which is a most basic principle of scientific research. It is widely recognized and understood that results in one mouse model may not translate to other models or humans. This is why the paper concludes with “The efficacy of combining these non-toxic treatments should be further studied to determine their potential for clinical use.”

6. The writers propose that patient derived xenograft models should be used instead of a syngeneic model. Both xenograft and syngeneic models are important systems used for cancer research, and each come with their own strengths and weaknesses. While xenograft models are certainly useful, they also come with an extreme caveat which is that the host animal lacks a functioning immune system (this is necessary so that the mouse host does not reject the human tumors). Since the immune system plays critical roles in cancer development, progression, invasion, metastasis, and response to treatment, we chose to use a syngeneic model, which allows for the use of an immunocompetent host, to test our therapy. The importance of the immune system in cancer progression is highlighted by the significant interest in immunotherapy development which is a current major focus of many cancer researchers. Although unknown at the time of this publication, it was particularly important to test the ketogenic diet in an immunocompetent model, since recent data has revealed that one mechanism of this therapy works via enhancing antitumor immunity [14]. It is also important to note that the writers suggest that use of inbred mice is “in contrast” to their preferred xenograft model system; however, this is inaccurate. Patient-derived xenografts are also often implanted into inbred strains of mice. Interestingly, patient-derived GBM xenographs have also responded remarkably well to ketogenic diet therapy [82][15].

7. Finally, the writers take point with the hypothesis put forth that many cancers seem to be less effective at utilizing ketones as a fuel source compared to healthy tissue. Tumors are remarkably resourceful. They will quickly adapt to utilize alternative nutrients to provide materials for their proliferative needs in whatever capacity possible. However, it is important to delineate metabolism in terms of energy production (ATP) versus biosynthesis (de novo synthesis of proteins, nucleotides, and lipids) as these processes are closely related but also independent.

Studies have shown that several cancers lack or have reduced ketolytic enzyme expression, as referenced in the text [16-18]. Furthermore, there are numerous reports of mitochondrial abnormalities across cancer types, including abnormal mitochondrial number or morphology, partial or total cristolysis, mitochondrial DNA mutations, abnormal mitochondrial membrane lipid composition, altered mitochondrial membrane potential, and reduced or abnormal expression or activity of mitochondrial enzymes and electron transport chain complex components [19-36]. Considering the critical roles of each of these individual components in maintaining the integrity of oxidative phosphorylation-derived ATP production, we propose that it is unlikely that cells with such deficiencies could respire normally. (Note: the proposal is that respiration wouldn’t be normal, not that it would be entirely absent.) This hypothesis is further supported by the literature which widely demonstrates that cancer cells consistently produce large amounts of oxygen free radicals, another symptom of an impaired or uncoupled inner mitochondrial membrane and oxidative phosphorylation system [37]. Heat production is also a sign of uncoupled mitochondria, and again is something observed in tumors [36, 37].

Despite all of these confounding variables, it is common in the field to report levels of oxidative phosphorylation or to label a tumor as oxidative with a measure of oxygen consumption rate (OCR) [38]. OCR is an informative tool but there are caveats in this widely-used technique which need to be acknowledged. It is true that if a cell is respiring normally (and coupling electron flux to ATP production via oxidative phosphorylation), that cell will be consuming oxygen; however, the reverse is not necessarily true. Just because a cell is consuming oxygen, that is not necessarily coupled to ATP production, as this oxygen can be lost as oxygen free radicals or the energy produced coupled to heat production rather than ATP synthesis. As mentioned, both of these are observed at high rates in many tumors, on top of a plethora of other indicators which suggest impaired mitochondrial function. Some techniques which measure OCR give an indication of uncoupled respiration as well, but not all, and many fail to account for free radical generation. We propose that OCR alone is not an adequate measure of oxidative phosphorylation capacity for a cancer cell. Considering all of this, respiration may be reduced or deficient to some degree in many cancers, especially those with marked mitochondrial defects, of which there are many – despite the fact that many of them still do consume oxygen.

For these reasons, it seems likely that ketones, which are metabolized exclusively in the mitochondria, may not provide as efficient an energetic fuel for cancers as other metabolites such as glucose, as there may be a deficiency in utilizing their oxidation to promote normal mitochondrial ATP production via oxidative phosphorylation. For example, Maurer et al demonstrated that ketones could rescue healthy brain cells from glucose-withdrawal induced cell death, but not the 5 different brain cancer cell lines tested, even though those brain cancer cells expressed ketone utilization enzymes [38]. Also, we must consider that mitochondrial oxidative phosphorylation capacity appears diminished (but not non-functional) in many tumors, so there will almost certainly be a continuum of responses to the ketogenic diet and indeed some tumors will likely be naturally resistant to the diet, perhaps even promoted by the diet, or will be able to adapt to or become resistant to the diet. More research is on-going, and needed.

It is critical to recognize that these potential deficiencies in mitochondrial respiration of ketones would not affect the efficiency of mitochondrial metabolism of ketones for biosynthesis. Rather, mitochondrial metabolism for biomass is often heightened to support rapid proliferation [39]. Indeed, ketones are likely metabolized for their carbons in many tumors and these carbons are incorporated into the new biomolecules being produced to form new cancer cells. This has been demonstrated in a few studies with carbon labeling of ketone bodies in tumors in vivo [40]. Certainly, carbons from ketones can make it into the tumor and be metabolized for biosynthesis, at least in those tumors that are not lacking expression of ketolytic enzymes. There is nothing about the hypothesis that ketones may be inefficient energy substrates for cancer that would preclude them from being efficient biomass substrates for cancer, as has been reported in many of the studies the writers cite. But just because you may be unable to target both biomass and energy production by switching to ketosis, doesn’t mean that targeting one path would not be potentially beneficial.

The writers oddly critique this paper for not acknowledging research that was not yet published at the time of this paper’s publication, which is highly unusual. In fact, to rebut the comment made in the paper that the literature suggests ketones are inefficient fuels for many cancers, the writers cite 7 papers, 5 of which were not yet published at the time that this article went to press. In doing so, they also fail to acknowledge the literature which contradicts their points (some examples include [38, 41-45]). Even some of the papers the writers cite in their rebuttal do not support their comments. For example, they cite Schwartz, et al to support their statement that the literature does not suggest a deficiency of ketone metabolism in cancer, although that paper reported that the expression of rate-limiting ketolytic enzymes were low or very low in 15 of 22 malignant glioma samples tested [16].

We are pleased to see that this field has been growing rapidly in recent years since this publication, and we are thankful that studies are being published which increase our knowledge of ketone metabolism in cancers, and the ketogenic diet as a potential therapy, including situations or cancer-types where these therapies may be contraindicated [46-48]. Indeed, in the years since this publication came out, it has become more clear that there are likely specific cancers which would not benefit from ketogenic therapy [49]. As mentioned in our paper we agree that additional research is necessary and ongoing. However, there have been numerous studies published demonstrating anti-cancer efficacy or encouraging results with ketogenic therapies in multiple models of varied cancer types, including both syngeneic and xenograft models, as well as in a few human reports, from a diverse group of scientists in the U.S. and abroad [14, 15, 38, 45, 50-85]. Because of these results, the ketogenic diet has or is being investigated at present in approximately 20 clinical trials in the U.S. (https://clinicaltrials.go...), also in clinical trails abroad, and continues to be investigated in additional pre-clinical models.

Finally, it is important to have a realistic expectation of efficacy in cancer research. The writers refer to a small, human trial in GBM where patients exhibited disease progression while on the ketogenic diet, with the implication being that this demonstrated the diet to be ineffective [86]. Progression of disease under treatment is commonplace for almost all therapeutics, especially in GBM. But most importantly, the study was not powered to make conclusions about treatment efficacy. It is impossible to know if the diet affected the rate of disease progression in these patients. The writers’ comments suggest expectation of remission or cessation of tumor progression for a new therapeutic. Sadly, this is not a realistic expectation for many aggressive cancers. We agree with the writers in hoping that one day there will be an effective battery of treatments that can be employed such that this dream becomes a reality.

References:
1. Huysentruyt LC, Mukherjee P, Banerjee D, Shelton LM, Seyfried TN: Metastatic cancer cells with macrophage properties: evidence from a new murine tumor model. International journal of cancer 2008, 123(1):73-84.
2. Khanna C, Hunter K: Modeling metastasis in vivo. Carcinogenesis 2005, 26(3):513-523.
3. Bennani-Baiti N, Walsh D: Animal models of the cancer anorexia-cachexia syndrome. Support Care Cancer 2011, 19(9):1451-1463.
4. Huysentruyt LC, Shelton LM, Seyfried TN: Influence of methotrexate and cisplatin on tumor progression and survival in the VM mouse model of systemic metastatic cancer. International journal of cancer Journal international du cancer 2010, 126(1):65-72.
5. Mujic A, Hunn A, Taylor A, Lowenthal R: Extracranial metastases of a glioblastoma multiforme to the pleura, small bowel and pancreas. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 2006, 13(1f3b0330-abff-26d5-e895-114895697c3a):677-758.
6. Saad A, Sachs J, Turner C, Proctor M, Marcus K, Wang L, Lidov H, Ullrich N: Extracranial metastases of glioblastoma in a child: case report and review of the literature. Journal of pediatric hematology/oncology 2007, 29(1a0a3578-0e23-3b70-071f-1148956b20b6):190-194.
7. Taha M, Ahmad A, Wharton S, Jellinek D: Extra-cranial metastasis of glioblastoma multiforme presenting as acute parotitis. British journal of neurosurgery 2005, 19(63cde369-77ce-9f69-4ebf-114896533cc0):348-399.
8. Schultz S, Pinsky G, Wu N, Chamberlain M, Rodrigo A, Martin S: Fine needle aspiration diagnosis of extracranial glioblastoma multiforme: Case report and review of the literature. CytoJournal 2005, 2(54668d8c-0c83-586e-5004-1148956cc24f):19.
9. Zhen L, Yufeng C, Zhenyu S, Lei X: Multiple extracranial metastases from secondary glioblastoma multiforme: a case report and review of the literature. Journal of neuro-oncology 2010, 97(27ff469f-258b-85ed-4329-1148956d5294):451-458.
10. Gotway M, Conomos P, Bremner R: Pleural metastatic disease from glioblastoma multiforme. Journal of thoracic imaging 2011, 26(9f9eef46-fadc-553a-b524-1148965398be):8.
11. Chen H, Shah AS, Girgis RE, Grossman SA: Transmission of glioblastoma multiforme after bilateral lung transplantation. J Clin Oncol 2008, 26(19):3284-3285.
12. Armanios M, Grossman S, Yang S, White B, Perry A, Burger P, Orens J: Transmission of glioblastoma multiforme following bilateral lung transplantation from an affected donor: case study and review of the literature. Neuro-oncology 2004, 6(ba1be63c-6173-ea0a-8891-1148971f6c38):259-322.
13. Shelton LM, Mukherjee P, Huysentruyt LC, Urits I, Rosenberg JA, Seyfried TN: A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion. Journal of neuro-oncology 2010, 99(2):165-176.
14. Lussier DM, Woolf EC, Johnson JL, Brooks KS, Blattman JN, Scheck AC: Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer 2016, 16:310.
15. Martuscello RT, Vedam-Mai V, McCarthy DJ, Schmoll ME, Jundi MA, Louviere CD, Griffith BG, Skinner CL, Suslov O, Deleyrolle LP et al: A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma. Clin Cancer Res 2016, 22(10):2482-2495.
16. Chang HT, Olson LK, Schwartz KA: Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy. Nutrition & metabolism 2013, 10(1):47.
17. Tisdale M, Brennan R: Loss of acetoacetate coenzyme A transferase activity in tumours of peripheral tissues. British journal of cancer 1983, 47(2):293-297.
18. Sawai M, Yashiro M, Nishiguchi Y, Ohira M, Hirakawa K: Growth-inhibitory effects of the ketone body, monoacetoacetin, on human gastric cancer cells with succinyl-CoA: 3-oxoacid CoA-transferase (SCOT) deficiency. Anticancer research 2004, 24(4):2213-2217.
19. Kiebish MA, Han X, Seyfried TN: Examination of the brain mitochondrial lipidome using shotgun lipidomics. Methods in molecular biology 2009, 579:3-18.
20. Frezza C, Pollard P, Gottlieb E: Inborn and acquired metabolic defects in cancer. Journal of molecular medicine (Berlin, Germany) 2011, 89(d67636e7-b12c-4175-a30d-9c7fa4d3645d):213-233.
21. Chen EI: Mitochondrial dysfunction and cancer metastasis. J Bioenerg Biomembr 2012, 44(6):619-622.
22. Modica-Napolitano J, Singh K: Mitochondrial dysfunction in cancer. Mitochondrion 2004, 4:755-817.
23. Arismendi-Morillo G, Castellano-Ramirez A: Ultrastructural mitochondrial pathology in human astrocytic tumors: potentials implications pro-therapeutics strategies. Journal of electron microscopy 2008, 57:33-42.
24. Kiebish M, Han X, Cheng H, Chuang J, Seyfried T: Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. Journal of lipid research 2008, 49:2545-2601.
25. Hall A, Meyle KD, Lange MK, Klima M, Sanderhoff M, Dahl C, Abildgaard C, Thorup K, Moghimi SM, Jensen PB et al: Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene. Oncotarget 2013, 4(4):584-599.
26. Chen J-Q, Russo J: Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells. Biochimica et biophysica acta 2012, 1826(ba802457-b23c-2ea6-313c-9c7fa5833052):370-754.
27. Owens KM, Kulawiec M, Desouki MM, Vanniarajan A, Singh KK: Impaired OXPHOS complex III in breast cancer. PLoS One 2011, 6(8):e23846.
28. Jahnke VE, Sabido O, Defour A, Castells J, Lefai E, Roussel D, Freyssenet D: Evidence for mitochondrial respiratory deficiency in rat rhabdomyosarcoma cells. PLoS One 2010, 5(1):e8637.
29. Lopez-Rios F, Sanchez-Arago M, Garcia-Garcia E, Ortega AD, Berrendero JR, Pozo-Rodriguez F, Lopez-Encuentra A, Ballestin C, Cuezva JM: Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res 2007, 67(19):9013-9017.
30. Yadav N, Chandra D: Mitochondrial DNA mutations and breast tumorigenesis. Biochimica et biophysica acta 2013, 1836(2):336-344.
31. Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH et al: mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci U S A 2005, 102(3):719-724.
32. Wu M, Neilson A, Swift AL, Moran R, Tamagnine J, Parslow D, Armistead S, Lemire K, Orrell J, Teich J et al: Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. American journal of physiology Cell physiology 2007, 292(1):C125-136.
33. Pagano G, Talamanca AA, Castello G, Cordero MD, d'Ischia M, Gadaleta MN, Pallardo FV, Petrovic S, Tiano L, Zatterale A: Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: toward mitochondria-targeted clinical strategies. Oxid Med Cell Longev 2014, 2014:541230.
34. Yu M, Wan Y, Zou Q: Reduced mitochondrial DNA copy number in Chinese patients with osteosarcoma. Transl Res 2013, 161(3):165-171.
35. Yu M, Zhou Y, Shi Y, Ning L, Yang Y, Wei X, Zhang N, Hao X, Niu R: Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life 2007, 59(7):450-457.
36. Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B: Somatic mutations of the mitochondrial genome in human colorectal tumours. Nature genetics 1998, 20(3):291-293.
37. Schumacker P: Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer cell 2006, 10:175-181.
38. Maurer G, Brucker D, Bähr O, Harter P, Hattingen E, Walenta S, Mueller-Klieser W, Steinbach J, Rieger J: Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC cancer 2011, 11:315.
39. Gillies R, Robey I, Gatenby R: Causes and consequences of increased glucose metabolism of cancers. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2008, 49 Suppl 2.
40. Eloqayli H, Melo TM, Haukvik A, Sonnewald U: [2,4-(13)C]beta-hydroxybutyrate metabolism in astrocytes and C6 glioblastoma cells. Neurochem Res 2011, 36(8):1566-1573.
41. Barbara AM, Nicholas P, Allan MR, Robert AJC: THE INHIBITION OF MALIGNANT CELL GROWTH BY KETONE BODIES. Australian Journal of Experimental Biology and Medical Science 1979, 57.
42. Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD: Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer cell international 2009, 9:14.
43. Fine E, Segal-Isaacson C, Feinman R, Herszkopf S, Romano M, Tomuta N, Bontempo A, Negassa A, Sparano J: Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition 2012, 28(10):1028-1035.
44. Skinner R, Trujillo A, Ma X, Beierle E: Ketone bodies inhibit the viability of human neuroblastoma cells. Journal of pediatric surgery 2009, 44(1):212.
45. Poff AM, Ari C, Arnold P, Seyfried TN, D'Agostino DP: Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International journal of cancer 2014:1711-1720.
46. Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell R, Chiavarina B, Frank P, Flomenberg N, Howell A, Martinez-Outschoorn U et al: Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell cycle 2010, 9(17):3506-3514.
47. Xia S, Lin R, Jin L, Zhao L, Kang HB, Pan Y, Liu S, Qian G, Qian Z, Konstantakou E et al: Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth. Cell Metab 2017, 25(2):358-373.
48. Liskiewicz AD, Kasprowska D, Wojakowska A, Polanski K, Lewin-Kowalik J, Kotulska K, Jedrzejowska-Szypulka H: Long-term High Fat Ketogenic Diet Promotes Renal Tumor Growth in a Rat Model of Tuberous Sclerosis. Sci Rep 2016, 6:21807.
49. Jansen N, Walach H: The development of tumours under a ketogenic diet in association with the novel tumour marker TKTL1: A case series in general practice. Oncol Lett 2016, 11(1):584-592.
50. Tisdale MJ, Brennan RA, Fearon KC: Reduction of weight loss and tumour size in a cachexia model by a high fat diet. British journal of cancer 1987, 56(1):39-43.
51. Tisdale MJ, Brennan RA: A comparison of long-chain triglycerides and medium-chain triglycerides on weight loss and tumour size in a cachexia model. British journal of cancer 1988, 58(5):580-583.
52. Beck SA, Tisdale MJ: Effect of insulin on weight loss and tumour growth in a cachexia model. Br J Cancer 1989, 59(5):677-681.
53. Nebeling LC, Miraldi F, Shurin SB, Lerner E: Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. Journal of the American College of Nutrition 1995, 14(2):202-208.
54. Nebeling LC, Lerner E: Implementing a ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer. Journal of the American Dietetic Association 1995, 95(6):693-697.
55. Mavropoulos J, Isaacs W, Pizzo S, Freedland S: Is there a role for a low-carbohydrate ketogenic diet in the management of prostate cancer? Urology 2006, 68(1):15-18.
56. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN: The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutrition & metabolism 2007, 4:5.
57. Freedland S, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson W, Cohen P, Hwang D, Peterson B, Fields T et al: Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. The Prostate 2008, 68(1):11-19.
58. Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, Voelker H, Thiede A, Coy J: Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC cancer 2008, 8:122.
59. Mavropoulos J, Buschemeyer W, Tewari A, Rokhfeld D, Pollak M, Zhao Y, Febbo P, Cohen P, Hwang D, Devi G et al: The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer prevention research (Philadelphia, Pa) 2009, 2(6):557-565.
60. Masko E, Thomas J, Antonelli J, Lloyd J, Phillips T, Poulton S, Dewhirst M, Pizzo S, Freedland S: Low-carbohydrate diets and prostate cancer: how low is "low enough"? Cancer prevention research (Philadelphia, Pa) 2010, 3(9):1124-1131.
61. Stafford P, Abdelwahab M, Kim DY, Preul M, Rho J, Scheck A: The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutrition & metabolism 2010, 7:74.
62. Schmidt M, Pfetzer N, Schwab M, Strauss I, Kämmerer U: Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. Nutrition & metabolism 2011, 8(1):54.
63. Scheck A, Abdelwahab M, Fenton K, Stafford P: The ketogenic diet for the treatment of glioma: Insights from genetic profiling. Epilepsy research 2011, 100:327-337.
64. Kim H, Masko E, Poulton S, Kennedy K, Pizzo S, Dewhirst M, Freedland S: Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer. BJU international 2012, 110(7):1062-1069.
65. Abdelwahab M, Fenton K, Preul M, Rho J, Lynch A, Stafford P, Scheck A: The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PloS one 2012, 7.
66. Caso J, Masko EM, Ii JA, Poulton SH, Dewhirst M, Pizzo SV, Freedland SJ: The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model. The Prostate 2013, 73(5):449-454.
67. Allen BG, Bhatia SK, Buatti JM, Brandt KE, Lindholm KE, Button AM, Szweda LI, Smith BJ, Spitz DR, Fath MA: Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clinical cancer research : an official journal of the American Association for Cancer Research 2013, 19(14):3905-3913.
68. Poff AM, Ari C, Seyfried TN, D'Agostino DP: The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PloS one 2013, 8(6):e65522.
69. Poff AM, Ward N, Seyfried TN, Arnold P, D'Agostino DP: Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy. PLoS One 2015, 10(6):e0127407.
70. Schroeder U, Himpe B, Pries R, Vonthein R, Nitsch S, Wollenberg B: Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer. Nutr Cancer 2013, 65(6):843-849.
71. Champ CE, Palmer JD, Volek JS, Werner-Wasik M, Andrews DW, Evans JJ, Glass J, Kim L, Shi W: Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol 2014, 117(1):125-131.
72. Rieger J, Bahr O, Maurer GD, Hattingen E, Franz K, Brucker D, Walenta S, Kammerer U, Coy JF, Weller M et al: ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol 2014, 44(6):1843-1852.
73. Shukla SK, Gebregiworgis T, Purohit V, Chaika NV, Gunda V, Radhakrishnan P, Mehla K, Pipinos, II, Powers R, Yu F et al: Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab 2014, 2:18.
74. Gluschnaider U, Hertz R, Ohayon S, Smeir E, Smets M, Pikarsky E, Bar-Tana J: Long-chain fatty acid analogues suppress breast tumorigenesis and progression. Cancer Res 2014, 74(23):6991-7002.
75. Healy ME, Chow JD, Byrne FL, Breen DS, Leitinger N, Li C, Lackner C, Caldwell SH, Hoehn KL: Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine. J Hepatol 2015, 62(3):599-606.
76. Morscher RJ, Aminzadeh-Gohari S, Feichtinger RG, Mayr JA, Lang R, Neureiter D, Sperl W, Kofler B: Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model. PLoS One 2015, 10(6):e0129802.
77. Hao GW, Chen YS, He DM, Wang HY, Wu GH, Zhang B: Growth of human colon cancer cells in nude mice is delayed by ketogenic diet with or without omega-3 fatty acids and medium-chain triglycerides. Asian Pac J Cancer Prev 2015, 16(5):2061-2068.
78. Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC: The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model. PLoS One 2015, 10(6):e0130357.
79. Stemmer K, Zani F, Habegger KM, Neff C, Kotzbeck P, Bauer M, Yalamanchilli S, Azad A, Lehti M, Martins PJ et al: FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. Diabetologia 2015, 58(10):2414-2423.
80. Branca JJ, Pacini S, Ruggiero M: Effects of Pre-surgical Vitamin D Supplementation and Ketogenic Diet in a Patient with Recurrent Breast Cancer. Anticancer Res 2015, 35(10):5525-5532.
81. Tan-Shalaby JL, Carrick J, Edinger K, Genovese D, Liman AD, Passero VA, Shah RB: Modified Atkins diet in advanced malignancies - final results of a safety and feasibility trial within the Veterans Affairs Pittsburgh Healthcare System. Nutr Metab (Lond) 2016, 13:52.
82. Woolf EC, Scheck AC: The Ketogenic Diet for the Treatment of Malignant Glioma. Journal of lipid research 2014.
83. Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, Seyfried TN: Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutrition & metabolism 2010, 7:33.
84. Klement RJ, Champ CE, Otto C, Kammerer U: Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis. PLoS One 2016, 11(5):e0155050.
85. Winter SF, Loebel F, Dietrich J: Role of ketogenic metabolic therapy in malignant glioma: A systematic review. Crit Rev Oncol Hematol 2017, 112:41-58.
86. Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, Kurniali PC, Hord NG, Noel M: Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab 2015, 3:3.