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4-Year Long Progression-Free and Symptom-Free Survival of a Patient with Recurrent Glioblastoma Multiforme: A Case Report of the Paleolithic Ketogenic Diet (PKD) Used as a Stand-Alone Treatment After Failed Standard Oncotherapy

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Abstract and Figures

Studies in animal models have suggested that the ketogenic diet may be effective in the treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far, failed to show benefits in cancer survival or in any other hard clinical endpoints of the disease. This paper presents a case report of a patient with glioblastoma multiforme. The patient had initially been treated with standard oncotherapy including surgery, radiotherapy and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the glioblastoma seven months later. Subsequently, the patient refused radiotherapy and chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy. Following the adoption of the PKD, progression of the disease has been completely halted. At the time of writing, the patient has remained in remission for 48 months, is without side-effects and experiences an excellent quality of life without the use of any drugs.
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4-year long progression-free and symptom-free survival of a patient with recurrent
glioblastoma multiforme: A case report of the Paleolithic Ketogenic Diet (PKD) used as
a stand-alone treatment after failed standard oncotherapy
Csaba Tóth1, Andrea Dabóczi1, Madhvi Chanrai2, Mária Schimmer1, Katalin Horváth3,
Zsófia Clemens1*
1 International Center for Medical Nutritional Intervention - Paleomedicina Hungary Ltd.,
Budapest, Hungary
2 Independent researcher
3 County Hospital Zala, Zalaegerszeg, Department of Radiology and Radioisotope Diagnostics
*Corresponding author: Zsófia Clemens, PhD
Keywords: glioblastoma, brain tumor, paleolithic diet, ketogenic diet, paleolithic ketogenic
diet, metabolic therapy, intestinal permeability, cancer treatment
Studies in animal models have suggested that the ketogenic diet may be effective in the
treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far,
failed to show benefits in cancer survival or in any other hard clinical endpoints of the
disease. This paper presents a case report of a patient with glioblastoma multiforme. The
patient had initially been treated with standard oncotherapy including surgery, radiotherapy
and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the
glioblastoma seven months later. Subsequently, the patient refused radiotherapy and
chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy.
Following the adoption of the PKD, progression of the disease has been completely halted. At
the time of writing, the patient has remained in remission for 48 months, is without side-
effects and experiences an excellent quality of life without the use of any drugs.
In recent years there has been a surge of interest in the use of ketogenic diets as a potential
treatment for cancer (Klement, 2017). The idea that ketogenic diets may have antitumor
effects was initially put forward following the positive findings that emerged from animal
studies (Zhou et al., 2007). Clinical studies with the ketogenic diet, have however, repeatedly
failed to show benefits in any clinical hard endpoints such as progression-free survival.
The authors of this paper have adopted an evolutionary approach to health and to the
treatment of disease. Hence, we have developed and have been using the paleolithic ketogenic
diet (PKD) in the treatment of several chronic diseases in more than 5000 patients for the last
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© 2020 by the author(s). Distributed under a Creative Commons CC BY license.
10 years. The PKD is a diet that is based on animal fat and meat and is similar to the diet that
was originally proposed by Voegtlin (1975).
In the classic ketogenic diet, the source of the foods is not stipulated; whereas in the PKD the
source of the fats and proteins is of the utmost importance. In practical terms this means that
the PKD excludes all dairy products, cereal grains, plant oils, nightshades, legumes and
dietary supplements; i.e. all foods that were not routinely available before the advent of
agriculture 10,000 years ago.
The classic ketogenic diet (and its variants), typically contain unrestricted amounts of dairy
products, nuts and plant oils, which are normally excluded in the PKD. In our opinion, this
difference accounts for the additional benefits conferred by the PKD as compared to the
classic ketogenic diet. We believe that excluding the non-PKD food components results in the
normalization of intestinal permeability, which is a critical factor in the mechanism of action
of the PKD in cancer (Tóth et al., 2017).
Thus far, we have published several case reports of patients who have been successfully
treated with the PKD. These include: type 2 (Tóth and Clemens, 2015a) and type 1 diabetes
(Tóth and Clemens, 2014; 2015b); Crohn’s disease (Tóth et al, 2016); Gilbert’s syndrome
(Tóth and Clemens, 2015c); epilepsy (Clemens et al., 2013, 2015); complete reversal of
cervical intraepithelial neoplasia (Tóth et al., 2018); halted progression of soft palate cancer
(Tóth and Clemens, 2016) and regression of rectal cancer ((Tóth and Clemens, 2017)
Here we present a case report of a patient with glioblastoma multiforme. Initially, the patient
had been treated with standard oncotherapy including surgery, radiotherapy and
chemotherapy. Despite standard treatment, the patient experienced a recurrence of the
glioblastoma seven months later. Subsequently, the patient refused standard oncotherapy and
opted to use the PKD as a stand-alone therapy. Since initiating the PKD, progression of the
disease has been completely halted. At the time of writing, the patient has remained in
remission for 4 years, and that too without the use of any drugs. Furthermore, besides being
progression-free, the patient has also been symptom-free.
The medical history of the patient included bladder cancer operated in 2012. He also had
hypertension treated with antihypertensives. The patient presented with severe headache in
late January 2016 at the age of 52 years old. A subsequent MRI on the 28th of January 2016
showed a cystic lesion of 44 x 60 x 55 mm in the right parieto-temporo-occipital region with
T2 hyperintensity, and edema resulting in a 10-mm midline shift at the level of the lateral
ventricles (Fig. 1.). Histopathology showed polymorph cells, including giant and multi-
nucleated cells as well as necrotic tissue. Immunohistochemistry showed GFAP positivity, Ki-
67 labeling above 15% and significant p53 positivity suggesting glioblastoma multiforme.
Subtotal surgery was performed the next day. Histopathology indicated glioblastoma
multiforme. A follow-up CT scan on 02 Mar 2016 showed a cystic mass of 49 x 29.9 mm
containing another, 33 x 14 mm mass (Fig. 1.). Between March and May 2016 the patient
underwent radiochemotherapy along with temozolomide treatment. An MRI in August 2016
showed tumor recurrence (Fig. 1.), whereupon the patient decided to stop standard treatment
and contacted us for medical guidance.
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Paleolithic ketogenic diet
In agreement with the patient, we started the PKD on the 2nd September 2016. The PKD is an
animal fat-meat based diet with a fat:protein ratio of approximately 2:1 (in grams). The diet
excludes cereal grains, dairy products, nightshades, legumes, plant oils (including coconut oil
and olive oil), nuts, refined sugars, artificial sweeteners, food additives and all types of dietary
supplements. Red and fatty meats were the predominant foods in the patient’s diet, with
regular consumption of organ meat from cattle and pork as well. Although the PKD may
include some plant foods in certain cases, in this patient’s case all plant foods were excluded
in order to maximize the effectiveness of the PKD. The patient had two meals a day. He was
suggested to eat when hungry, drink when thirsty, and to eat until satiation. The patient has
been working full time during his entire follow-up. He was not doing any major exercise or
The patient was under our close control with frequent personal visits, as well as e-mail and
phone communication.
Laboratory workup and urinary ketones
The patient was followed-up with regular laboratory workups and brain MRI. The patient
occasionally checked urinary ketones for his own feedback but did not keep track of these
monitoring of urinary ketones
HDL chol.
LDL chol.
Uric acid
Table 1.
Laboratory workup: metabolic parameters. The value that can be regarded as a positive outlier
is indicated in red.
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Table 2
Laboratory workup: minerals, ions and vitamins. Values that can be regarded as negative
outliers are indicated in blue.
Table 3.
Laboratory workup: inflammatory markers. Values that can be regarded as positive outliers
are indicated in red.
Glucose levels were low except for the first measurement shortly after starting the diet.
Cholesterol, HDL and LDL cholesterol tended to be slightly elevated. Triglyceride and uric
acid were in the normal range. Mineral, ion and vitamin levels were also in the normal range
except for the iron being slightly low on two measurements and vitamin D being low upon the
last measurement (Table 2.). Inflammatory markers were generally low except for the ESR
being elevated on three measurements (Table 3.). Blood work was used to give feedback to
the patient on how to fine-tune the diet.
Adherence level
The patient showed a generally high level of adherence throughout the entire follow-up. This
was ascertained by blood work and feedback from the patient. Although the patient did not
deviate from the major rules of the PKD he tended to overeat periodically. This may explain
the TSH being closer to the upper limit of the normal range, which in our experience indicates
relative overeating (Table 1.). The patient also reported having consumed coffee from time to
time despite recommendations against drinking coffee. This was reflected in the slightly
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decreased iron levels; coffee consumption has a known effect of lowering iron (Morck et al.,
MRI scans
During the follow-up of 48 months, nine consecutive MRI scans were performed 3-6 months
apart. Each of them showed stable sizes of the tumor and the associated cyst (Figure 1.)
except for the last three MRI which indicated a small but gradual decrease in the size of the
General condition
Upon diet initiation the patient was mildly overweight (82 kg; 179 cm; BMI: 25.6). During
the first six months of the diet he was continuously losing weight. In six months, he lost 10 kg
(BMI: 22.5). Thereafter his weight fluctuated between 72 and 82 kg. The patient was free of
symptoms attributable to the brain tumor during the entire follow-up. The patient did not
experience epileptic seizures, nor any other neurological symptoms. The patient's blood
pressure normalized within one week of starting the diet. His antihypertensive medication was
therefore stopped, and his blood pressure has remained normal without medication. The
patient retained his physical strength and full work capacity during the entire follow-up. No
side-effects of the diet were seen during the 4-year follow-up.
Intestinal permeability test (PEG400 challenge test)
Intestinal permeability was assessed using a polyethylene glycol (PEG 400) challenge test
based on the method of Chadwick et al (1977). PEG 400 contains a mixture of inert water-
soluble molecules of at least 11 different sizes. PEG 400 is also nontoxic, not degraded by
intestinal bacteria, not metabolized by tissues, and rapidly excreted in urine. After a 3.0-gram
oral dose of PEG, the subject makes a six-hour urine collection. Components were separated
and quantified by high-performance liquid chromatography (HPLC). The percentage of each
fraction of PEG excreted over 6 hours is calculated.
The PEG400 challenge test that was performed in January 2018 (at 17 months on the diet)
showed normal intestinal permeability for each of the molecular sizes (Figure 2). This timing
corresponded to a time period of not drinking coffee.
Patient Consent
Written informed consent was obtained from the patient for publication of this case report.
Glioblastoma is the most aggressive form of brain tumor in adults with a prognosis of a
median survival of 15 months after standard therapy (Thakkar et al., 2014). Currently, the
standard of care for glioblastoma includes surgical debulking along with concurrent
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chemotherapy and radiotherapy. After diagnosis, our patient was also treated with
temozolomide and concomitant radiotherapy, despite which a recurrence occurred after seven
months. The patient then stopped using standard oncotherapy and started using the PKD as a
stand-alone therapy. On this regime, the patient has been progression-free, symptom-free and
medicine-free for 38 months.
We have to emphasize that the PKD that we use in the treatment of cancer patients differs
from the classic version of the ketogenic diet that has traditionally been used in epilepsy
(Kossoff and Rho, 2009) as well as in clinical trials with cancer patients (for a review, see:
Klement et al., 2017). The main difference between the classic ketogenic diet (and its
variants) and the PKD is that while the classic ketogenic diet is based on plant oils, dairy
products and supplements, the PKD is based on animal meat, fat and organ meats.
Despite the popularity of the ketogenic diet, clinical studies with the classic ketogenic diet
repeatedly failed to provide evidence that it significantly improves cancer survival (Klement
et al., 2017). For example, the ERGO trial, a prospective trial of the ketogenic diet in
recurrent glioblastoma, failed to find a meaningful survival benefit (Rieger et al., 2014) while
in another study with the ketogenic diet in glioblastoma (van der Louw et al., 2019) overall
survival was only 12.8 months.
Currently, there are only case studies that report on long-term survival benefit in cancer due to
the ketogenic diet. One case study about two children with astrocytoma dates back to 1995
(Nebeling et al., 1995). Another study reported stable disease while the diet was sustained for
seven months (Zuccoli et al., 2010). A recent study using the ketogenic diet along with drugs
and hyperbaric oxygen therapy reported two-year survival in a glioblastoma patient (Elsakka
et al., 20l8), while another one reported complete therapeutic response in a breast cancer
patient (İyikesici et al., 2017).
Previously, we have published three cancer case reports, where the PKD resulted in regression
or stable disease. In a patient with recurrent cervical intraepithelial neoplasia, the PKD
resulted in complete reversal (Tóth et al., 2018). In another patient with an aggressive soft
palate cancer, the PKD resulted in progression-free status (Tóth and Clemens, 2016). The two
patients are still progression-free at 49 and 59 months after diet onset. In the third patient with
rectal cancer, the PKD resulted in a gradual regression while the PKD was highly adhered to
(Tóth and Clemens, 2016). We have also reported on other cancer patients with progression-
free survival beyond 2 years (Tóth et al., 2017; Clemens et al., 2019). These successful cases
share the PKD as stand-alone therapy administered to the patients (Tóth et al., 2017; Clemens
et al., 2019).
In general, ketogenic diets are thought to convey an anticancer effect through targeting the
Warburg phenomenon (Seyfried., 2012). Shifting away from a carbohydrate-based
metabolism toward a fat-based one has been shown to slow down tumor growth in animal
models although it has not been shown to stop cancer growth (Seyfried, 2012).
As we have recently pointed out (Tóth et al., 2017), the general lack of efficacy of the classic
ketogenic diet in cancer patients may be due to the fact that the classic ketogenic diet may not
convey all the benefits that are associated with the PKD.
Most importantly, a key beneficial mechanism of the PKD over other ketogenic diets is the
normalization of intestinal permeability (Tóth et al., 2017). Besides the metabolic
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improvements, it may be this amelioration of intestinal permeability that is crucial to halting
cancer progression. We have previously shown that it is the normalization of intestinal
permeability rather than the shift to ketosis that is pivotal in the PKD treatment of Crohn’s
disease and in autoimmune diseases (Tóth et al., 2017). In our experience, certain plant foods
prevent complete normalization of intestinal permeability, which is why all plant foods were
excluded from this patient’s diet.
In another patient with Hodgkin’s lymphoma, elevated intestinal permeability was shown to
normalize after switching from the classic ketogenic diet to the PKD (Clemens and Tóth,
Intestinal permeability is a membrane-related phenomenon that prevails at several levels of
the organization of the body. Membrane permeability is crucial in defining cell-to-cell
communication and in ensuring physiological contact inhibition within tissues. Loss of
contact inhibition is known to be associated with a cancerous transformation of tissues
(Kojima, 1993). Increased intestinal permeability has been suggested to promote
tumorigenesis (Lin et al., 2012) and has been described as being associated with various
tumor types (e.g. Soler et al 1999; Melichar, 2007). In 2016 we provided evidence that
increased intestinal permeability normalized on the PKD in a Crohn’s disease patient in
parallel with full recovery from the disease (Tóth et al., 2016). Yet, so far, no dietary or other
interventions have resulted in the normalization of intestinal membrane permeability
(Oldenwald and Turner, 2013).
Previous dietary intervention trials in cancer patients have not recognized the importance of
the intestinal permeability. Also, attempts, until now, have failed to reverse elevated intestinal
permeability. For example, a study with the regular paleolithic diet seemed to have no effect
on intestinal permeability, nor did it decrease inflammation (Boers et al., 2014).
In cancer patients, a high level of inflammation is regarded as a negative predictor for survival
(Strojnik et al., 2014). We put forward that normalizing intestinal permeability is key to
controlling inflammation through the application of PKD. Accordingly, we generally see a
decrease in the inflammatory markers after a shift toward the PKD (Tóth et al., 2018 and the
referenced case studies with the PKD). In our glioblastoma patient, intestinal permeability, as
measured by the PEG400 challenge test, also indicated normal intestinal permeability while
on the PKD. In our patient, inflammatory markers were generally low, although they
fluctuated to some degree during the follow-up. This fluctuation is likely to reflect periods of
drinking coffee. The lowest level of the inflammatory markers was seen in the blood work
from Jan 2019, a period corresponding to not drinking coffee. Inflammation level being
elevated by coffee is indicated by the literature (Zampelas et a., 2004) and is also in
accordance with our previous experience.
We are not aware of published studies on intestinal permeability as regards the classical
ketogenic diet. Yet, we assume that the classical ketogenic diet does not result in a
normalization of the intestinal permeability. We opine that the exclusion of all non-PKD food
items (dairy, vegetable oils and supplements which are typically found in the classical
ketogenic diet) is a key to normalize intestinal permeability. This notion is supported by a
previously published case where in a patient with Hodgkin’s lymphoma high intestinal
permeability was reversed after shifting from the classical ketogenic diet to the PKD and
stopping taking multiple supplements (Clemens and Tóth, 2019).
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Besides the fact that we used the PKD instead of the classic ketogenic diet, another important
difference from previous studies is that we used the dietary therapy as a stand-alone treatment.
Although it is generally believed that the standard care and dietary therapy can work in
synergy (Woolf and Scheck, 2015), we believe that it is the absence of chemotherapy and
radiotherapy which contributed to the unexpectedly long progression-free survival in our
Such an assumption agrees with the notion of Seyfried who pointed out that radiotherapy,
chemotherapy and the use of steroids may hinder the effect of a metabolic therapy and
paradoxically can result in boosting tumor growth through many different paths (Seyfried et
al, 2010). Seyfried also raised the possibility that in the future metabolic therapies may
become the standard of care in glioblastoma (Seyfried et al., 2019). We suggest that the
predominance of chemotherapy and radiotherapy in current oncotherapy may also have
prevented clinical trials of the ketogenic diet from major success.
Overall survival
Time to
progression on
the diet
Champ et al., 2014
4/6 patients alive at 12
5/6 patients
progressed at
12 months
Rieger et al., 2014
Median survival 32
weeks; range: 6-86+
All patients
Median: 5
weeks; range:
3-13 weeks
van der Louw et al.,
Median survival 12.8
months; range 9.8-18
Not reported
Woodhouse et al.,
2-year survival 26.7%
Not reported
Zuccoli et al., 2010
Not reported
10 months
(stopped the
diet at 7
Schwartz et al., 2015
Not reported
1 and 3 months
Elsakka et al., 2018
24 months (at the time of
writing the paper)
No progression
at 24 months
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Table 4.
Dietary intervention studies in glioblastoma multiforme. In the literature, the case with the
longest progression-free survival to date is 24 months, as documented by Elsakka et al (2018)
(24 months).
KD: ketogenic diet; R-KD: restricted ketogenic diet; MAD: modified Atkins diet; KMT:
ketogenic metabolic therapy
We put forward that the failure of previous ketogenic diet trials is not only down to the effect
of radiotherapy and chemotherapy that elevate blood glucose levels, but also to the fact that
chemotherapy (Keefe et al. 1997) and radiotherapy (Nejdfors et al., 2000) compromise the
intestinal barrier and thereby may be counterproductive in cancer treatment.
Medium survival for glioblastoma patients without treatment is three months (Schapira,
2007). As far as we know, our patient is the first glioblastoma patient in the literature
receiving a dietary therapy without any other treatment modalities (other than surgery).
Currently, with his 48-months progression-free survival and 56 months overall survival (from
diagnosis), he has the longest survival of all glioblastoma patients treated with a dietary
therapy and published in the literature (Table 4.).
Conflicts of Interest: The authors declare no conflict of interest.
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Figure 1.
MRI and CT scans performed during the course of the disease. Upper row: MRI showing the
tumor with the associated cyst upon diagnosis; postoperative CT; 4-weeks postoperative CT;
5-months postoperative MRI.
Manual outline of the cystic tumor is in red. Manual outline of the edema is in yellow.
Middle row and bottom row: MRI scan one month before starting the PKD and nine
consecutive follow-up MRI scans. Note that there is no change in the size of the tumor and
the associated cyst across the first seven MRI scans, but there is a small but gradual decrease
in the size of the cyst across the last three MRI scans. Red arrows indicate the cystic tumor
while the yellow arrows indicate the edema.
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Figure 2.
Result of the PEG400 challenge test. The test was done on 21 Jan 2018, at 17 months on the
diet. This timing corresponds to a time period of not drinking coffee. Note that intestinal
permeability was normal for all the molecular sizes.
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... The PKD differs from the classical KD in that it excludes food components that are not available in preagricultural times, and it supplies optimal amounts of micronutrients (73). Toth et al. have proven that the PKD has a considerable effect on soft palate cancer, rectal cancer, glioblastoma multiforme, and cervical intraepithelial neoplasia (72)(73)(74)(75). The researchers assume that this diet is evolutionarily advantageous for humans and has superior effectiveness compared to the KD in cancer management (72,73). ...
... Although diet has been used to improve immunotherapy and enhance the efficacy of chemotherapy or RT, it is still regarded as a nutritional supplement. Toth et al. (72)(73)(74)(75) have pointed out that nonsurgical therapies might hinder the effects of metabolic therapies and might even lead to the tumor progression in several studies. Therefore, the consideration of using diet therapy as a stand-alone treatment may bring unexpected results. ...
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Pancreatic cancer (PC) is a malignant tumor with high invasiveness, easy metastatic ability, and chemoresistance. Patients with PC have an extremely low survival rate due to the difficulty in early diagnosis. It is estimated that nearly 90% of PC cases are caused by environmental risk factors. Approximately 50% of PC cases are induced by an unhealthy diet, which can be avoided. Given this large attribution to diet, numerous studies have assessed the relationship between various dietary factors and PC. This article reviews three beneficial diets: a ketogenic diet (KD), a Mediterranean diet (MD), and a low-sugar diet. Their composition and impact mechanism are summarized and discussed. The associations between these three diets and PC were analyzed, and we aimed to provide more help and new insights for the prevention and treatment of PC.
... Furthermore, Paleolithic eating patterns have been associated with gut microbial diversity [24] and reduction of sporadic colorectal adenoma incidence rates [25]. Several case reports by the Hungarian group led by Zsofia Clemens and Csaba Tóth have shown that a ketogenic version of a Paleolithic diet excluding all plant fats and focusing on "nose-to-tail" eating of animals may exert beneficial effects against different tumor entities [26][27][28][29]. However, to date, no clinical study has investigated a Paleolithic diet during oncological standard treatment. ...
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Evolutionary principles are rarely considered in clinical oncology. We here aimed to test the feasibility and effects of a dietary and physical activity intervention based on evolutionary considerations in an oncological setting. A total of 13 breast cancer patients referred to our clinic for curative radiotherapy were recruited for this pilot study. The women were supposed to undertake a "Paleolithic lifestyle" (PL) intervention consisting of a Paleolithic diet and daily outdoor activity of at least 30 min duration while undergoing radiotherapy. Body composition was measured weekly by bioimpedance analysis. Blood parameters were assessed before, during, and at the end of radiotherapy. A control group on an unspecified standard diet (SD) was assigned by propensity score matching. A total of eleven patients completed the study. The majority of patients (64%) reported feeling good or very good during the intervention. The intervention group experienced an average decrease of 0.4 kg body weight (p < 0.001) and 0.34 kg (p < 0.001) fat mass per week, but fat-free and skeletal muscle mass were not significantly affected. Vitamin D levels increased slightly from 23.8 (11-37.3) ng/ml to 25.1 (22.6-41.6) ng/ml (p = 0.053). β-hydroxybutyrate levels were significantly increased and triglycerides and free T3 hormone levels significantly reduced by the PL intervention. This pilot study shows that adoption of a PL intervention during curative radiotherapy of breast cancer patients is feasible and able to reduce fat mass. Daily outdoor activity could eliminate vitamin D deficiency (vitamin D < 20 ng/ml). Future studies are needed to confirm these findings.
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Background: High-grade glioma cells consume mainly glucose and cannot compensate for glucose restriction. Apoptosis may potentially occur under carbohydrate restriction by a ketogenic diet (KD). We explored the feasibility and safety of KD during standard treatment of chemoradiation in patients with glioblastoma multiforme. Methods: A full liquid KD induced ketosis within 2 weeks before start of chemoradiation. After 6 weeks, the KD was modified with solid foods and medium-chain-triglyceride emulsions and used for an additional 6 weeks while maintaining ketosis. During the total study period (14 weeks), feasibility, safety, coping (both patient and partner), quality of life (QoL), neurological functioning and impairment were measured. Overall survival was analyzed with actuarial estimates. Results: Eleven patients started the study protocol, nine reached ketosis and six (67%) completed the study. Severe adverse effects did not occur. The majority of coping scores ranged from 3 to 6 on a 10-point scale at all timepoints; QoL, neurological functioning, and impairment did not essentially change over time; overall survival ranged between 9.8 and 19.0 months. Conclusion: KD was feasible and safe as an adjuvant to standard chemoradiation treatment of glioblastoma multiforme. A supportive partner and intensive counseling were essential for coping. Future research should identify possible beneficial effects on overall survival. Clinical trial registration: Netherlands Trial Registry: NTR5167 (registration date 29-01-2015),
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No major advances have been made in improving overall survival for glioblastoma (GBM) in almost 100 years. The current standard of care (SOC) for GBM involves immediate surgical resection followed by radiotherapy with concomitant temozolomide chemotherapy. Corticosteroid (dexamethasone) is often prescribed to GBM patients to reduce tumor edema and inflammation. The SOC disrupts the glutamate–glutamine cycle thus increasing availability of glucose and glutamine in the tumor microenvironment. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive GBM growth through substrate level phosphorylation in the cytoplasm and the mitochondria, respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability while elevating ketone bodies that are neuroprotective and non-fermentable. Information is presented from preclinical and case report studies showing how KMT could target tumor cells without causing neurochemical damage thus improving progression free and overall survival for patients with GBM.
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Outlook for cancer patients remains poor despite ”best available treatment” which includes surgery, chemotherapy and radiotherapy in most solid cancers. Genetic profiling, attempts to use matched chemotherapy and the use of high-cost biological therapies, so far, did result in no major breakthrough (1). Metabolic therapies have been suggested as a promising alternative option. Yet, clinical group studies that have been published, provide next to no evidence for a benefit in hard clinical endpoints of cancer. Previously, we put forward (2) that the apparent ineffectivity of the ketogenic diet in cancer is likely due to two factors. First, all published studies included cancer patients that also used chemo- and/or radiation therapy. Second, all group studies used the classical version of the ketogenic diet which is based on vegetable oils and dairy, an evolutionary maladapted, erroneous version of the ketogenic diet.
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Few advances have been made in overall survival for glioblastoma multiforme (GBM) in more than 40 years. Here, we report the case of a 38-year-old man who presented with chronic headache, nausea, and vomiting accompanied by left partial motor seizures and upper left limb weakness. Enhanced brain magnetic resonance imaging revealed a solid cystic lesion in the right partial space suggesting GBM. Serum testing revealed vitamin D deficiency and elevated levels of insulin and triglycerides. Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast. Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day. In addition to radiotherapy, temozolomide chemotherapy, and the KD (increased to 1,500 kcal/day at day 22), the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA). The patient also received levetiracetam (1,500 mg/day). No steroid medication was given at any time. Post-surgical histology confirmed the diagnosis of GBM. Reduced invasion of tumor cells and thick-walled hyalinized blood vessels were also seen suggesting a therapeutic benefit of pre-surgical metabolic therapy. After 9 months treatment with the modified SOC and complimentary ketogenic metabolic therapy (KMT), the patient’s body weight was reduced by about 19%. Seizures and left limb weakness resolved. Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D. This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies. As rapid regression of GBM is rare following subtotal resection and SOC alone, it is possible that the response observed in this case resulted in part from the modified SOC and other novel treatments. Additional studies are needed to validate the efficacy of KMT administered with alternative approaches that selectively increase oxidative stress in tumor cells while restricting their access to glucose and glutamine. The patient remains in excellent health (Karnofsky Score, 100%) with continued evidence of significant tumor regression.
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Triple-negative breast cancer (TNBC) is more aggressive and metastatic than other breast cancer types. Cytotoxic chemotherapy is presently the predominant systemic therapy for TNBC patients. This case report highlights the influence of metabolically supported chemotherapy (MSCT), ketogenic diet (KD), hyperthermia (HT), and hyperbaric oxygen therapy (HBOT) in an overweight 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast. The patient presented with an observable mass in her left breast detected during a physical examination in December 2015. Magnetic resonance imaging revealed a Breast Imaging Reporting and Data System Category 5 tumor and multiple lymphadenomegaly in the left axilla. A Tru-Cut biopsy led to the diagnosis of a triple-negative nuclear grade 2 invasive ductal carcinoma. The patient was admitted to ChemoThermia Oncology Center, Istanbul, Turkey in October 2016, and a whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) scan revealed a 77 mm x 55 mm primary tumor in her left breast, multiple left pectoral and axillary lymph nodes, multiple widespread liver masses, and an upper left nodular abdominal lesion. The patient received a treatment protocol consisting of MSCT, KD, HT, and HBOT. A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. The patient continued to receive this treatment protocol and in April 2017 underwent a mastectomy, which revealed a complete pathological response consistent with the response indicated by her PET-CT imaging. This single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV TNBC.
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Based on the hypothesis that cancer cells may not be able to metabolize ketones as efficiently as normal brain cells, the ketogenic diet (KD) has been proposed as a complementary or alternative therapy for treatment of malignant gliomas. We report here our experience in treating two glioma patients with an IRB-approved energy-restricted ketogenic diet (ERKD) protocol as monotherapy and review the literature on KD therapy for human glioma patients. An ERKD protocol was used in this pilot clinical study. In addition to the two patients who enrolled in this study, we also reviewed findings from 30 other patients, including 5 patients from case reports, 19 patients from a clinical trial reported by Rieger and 6 patients described by Champ. A total of 32 glioma patients have been treated using several different KD protocols as adjunctive/complementary therapy. The two patients who enrolled in our ERKD pilot study were monitored with twice daily measurements of blood glucose and ketones and daily weights. However, both patients showed tumor progression while on the ERKD therapy. Immunohistochemistry reactions showed that their tumors had tissue expression of at least one of the two critical mitochondrial ketolytic enzymes (succinyl CoA: 3-oxoacid CoA transferase, beta-3-hydroxybutyrate dehydrogenase 1). The other 30 glioma patients in the literature were treated with several different KD protocols with varying responses. Prolonged remissions ranging from more than 5 years to 4 months were reported in the case reports. Only one of these patients was treated using KD as monotherapy. The best responses reported in the more recent patient series were stable disease for approximately 6 weeks. No major side effects due to KD have been reported in any of these patients. We conclude that 1. KD is safe and without major side effects; 2. ketosis can be induced using customary foods; 3. treatment with KD may be effective in controlling the progression of some gliomas; and 4. further studies are needed to determine factors that influence the effectiveness of KD, whether as a monotherapy, or as adjunctive or supplemental therapy in treating glioma patients. NCT01535911.
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The main goal of this randomized controlled single-blinded pilot study was to study whether, independent of weight loss, a Palaeolithic-type diet alters characteristics of the metabolic syndrome. Next we searched for outcome variables that might become favourably influenced by a Paleolithic-type diet and may provide new insights in the pathophysiological mechanisms underlying the metabolic syndrome. In addition, more information on feasibility and designing an innovative dietary research program on the basis of a Palaeolithic-type diet was obtained. Thirty-four subjects, with at least two characteristics of the metabolic syndrome, were randomized to a two weeks Palaeolithic-type diet (n = 18) or an isoenergetic healthy reference diet, based on the guidelines of the Dutch Health Council (n = 14). Thirty-two subjects completed the study. Measures were taken to keep bodyweight stable. As primary outcomes oral glucose tolerance and characteristics of the metabolic syndrome (abdominal circumference, blood pressure, glucose, lipids) were measured. Secondary outcomes were intestinal permeability, inflammation and salivary cortisol. Data were collected at baseline and after the intervention. Subjects were 53.5 (SD9.7) year old men (n = 9) and women (n = 25) with mean BMI of 31.8 (SD5.7) kg/m2. The Palaeolithic-type diet resulted in lower systolic blood pressure (−9.1 mmHg; P = 0.015), diastolic blood pressure (−5.2 mmHg; P = 0.038), total cholesterol (−0.52 mmol/l; P = 0.037), triglycerides (−0.89 mmol/l; P = 0.001) and higher HDL-cholesterol (+0.15 mmol/l; P = 0.013), compared to reference. The number of characteristics of the metabolic syndrome decreased with 1.07 (P = 0.010) upon the Palaeolithic-type diet, compared to reference. Despite efforts to keep bodyweight stable, it decreased in the Palaeolithic group compared to reference (−1.32 kg; P = 0.012). However, favourable effects remained after post-hoc adjustments for this unintended weight loss. No changes were observed for intestinal permeability, inflammation and salivary cortisol. We conclude that consuming a Palaeolithic-type diet for two weeks improved several cardiovascular risk factors compared to a healthy reference diet in subjects with the metabolic syndrome. Trial registration Nederlands Trial Register NTR3002
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Advances in our understanding of glioma biology has led to an increase in targeted therapies in preclinical and clinical trials; however, cellular heterogeneity often precludes the targeted molecules from being found on all glioma cells, thus reducing the efficacy of these treatments. In contrast, one trait shared by virtually all tumor cells is altered (dysregulated) metabolism. Tumor cells have an increased reliance on glucose, suggesting that treatments affecting cellular metabolism may be an effective method to improve current therapies. Indeed, metabolism has been a focus of cancer research in the last few years, as many pathways long associated with tumor growth have been found to intersect metabolic pathways in the cell. The ketogenic diet (high fat, low carbohydrate and protein), caloric restriction, and fasting all cause a metabolic change; specifically, a reduction in blood glucose and an increase in blood ketones. We, and others, have demonstrated that these metabolic changes improve survival in animal models of malignant gliomas and can potentiate the anti-tumor effect of chemotherapies and radiation treatment. In this review we discuss the use of metabolic alteration for the treatment of malignant brain tumors.
Epithelial tissues act as barriers between two fluid compartments, and the epithelial barrier function is provided by the epithelial cells and the tight junctions (TJs) that connect them. We have shown previously that chronic treatment of a cultured epithelial monolayer with phorbol ester tumor promoters induces an increase in transepithelial paracellular permeability and produces tumor-like polyps, suggesting an association between TJ permeability and tumor formation. In this study, we analyzed the association between TJ permeability and formation of tumors in vivo. The permeability of the TJs was assessed in normal human and rat colon epithelia and in colon tumors by measuring the transepithelial electrical resistance, the paracellular flux rate of D-[ 14 C]mannitol and the electron microscopic evaluation of the penetration of the electron dense dye ruthenium red across the TJs. By these criteria, the TJs of human colon tumors, including carcinomas and adenomatous polyps, and the TJs of 1,2-dimethylhydrazine (DMH)-induced rat colon tumors were leakier than the TJs of normal colon. Treatment of rats with the carcinogen DMH induced a progressive increase in the number of aberrant colonic crypts, considered the putative pre-neoplastic colonic phenotype while increasing TJ permeability of the colon epithelium prior to the development of tumors. These results showed that increased TJ permeability of the colon epithelium and consequently a decrease in epithelial barrier function precede the development of colon tumors.