Friday, December 31, 2010

Sa·yo·na·ra 2010!

This tumor thing can get pretty crazy. Eat this, don't eat that. Do this, don't do that. It's hard to navigate this kind of life, trying to outsmart the tumor, there's no formula. Usually, I take it all in stride, and keep my knees bent for changes. Sometimes, however, it can be overwhelming, and I just want to give up. Luckily, those moments are few and far between, and I tend to feel better after a nap.

Lately, everything that my team (Danny, my mom & dad) reads show a calorie restricted diet to be the most effective natural treatment. That's not fun. Tonight, since it's NYE, I'm sure I'll indulge in one way or another. The tumor is always on my mind though. Even if I eat more than I should, I'll still be more careful than I would have been sans tumor. I'll never be able to go back to the days of ignorance and bliss.

Happy new year to everyone! Here's a mix of never been posted photos and some that you've probably seen before. What a wild year it was. Sorry for the lack of organization. The photos not in chronological order.




Adios 2010, you've been a crazy 365 days! Thanks for the memories. You challenged my strength, and my character, and I thank you for it. I've grown immeasurably.

Thursday, December 30, 2010

Broccoli Sprouts


Yesterday, the sunset was absolutely gorgeous and the quote at the gym was pretty inspirational too.

Also cool yesterday, I received an email from a couple. The wife has a stage 2 astrocytoma and they've been researching all kinds of alternative treatments. They're sharing all of their information with me which is incerdibly exciting! I love it that people contact me with all kinds of wonderful information, and stories. This blog has been such a wonderful gift in my life!

It's been long known that broccoli is a very healthy vegetable. It's pretty much a super star cancer fighter. According to John Hopkin's, the #1 brain tumor facility in the country, broccoli sprouts "pack 20 to 50 times the cancer-fighting punch of the mature broccoli plant."

Researchers are starting to use the compounds in broccoli to try and slow or even reverse the growth of brain tumors. It's still pretty early in the process to have any real definitive answers, but it's hopeful!

There's so much that we don't know about brain tumors and most medicine is based on treatment, not prevention. The truth is that we are what we eat. And no one is immune to disease. I sometimes wish that brain tumors were similar to HIV, in that you know how to prevent it. But if we can figure out how to slow or stop the growth of a brain tumor, that's as close as prevention as I think we're going to get for a while. It's a hard thing to study. I'm kind of a human rat, trying to learn what works for this tumor and what doesn't. I'm not sure if any that even makes sense. What does make sense, eating broccoli sprouts. Think about it...

Monday, December 27, 2010

Merry Christmas

I hope everyone had a wonderful Christmas! Sorry, I've been MIA. I fell off the grid for several days due to the holiday. Danny and I headed up to the island to celebrate Christmas with his and my family. It was so much fun having children of all ages around. We ate obnoxious amounts of delicious food, played games, and mostly visited with each other. It sounds odd but it was therapeutically exhausting. Does that make sense?

It's nice to get back to the house though. We made the mistake of leaving our Christmas tree in the living room while we were away. Live trees are wonderful...when they're watered.

Now it's back to the daily grind. I had my last speech therapy session for a couple of weeks. I'm now practicing what I've learned at home. Julie (the speech therapist) said that at this point in my recovery I need to continue to challenge myself. If I just sit on the couch watching daytime TV, my mind will grow stagnant.

I'm on a schedule to write a paper each week. They're short and sweet, but it's great practice to do an outline and organize my thoughts. Also, I read aloud for about 20 minutes a day, working on my fluency. I've been doing the papers for about 6 weeks and the fluency reading for about two weeks, now my new task is a word a week. I've decided to pick a word out of the dictionary and use it multiple times a day each week. This week's word is, austere. Julie said that I should only incorporate one new task every three or so weeks. With these tasks, I'm starting to fill up. This is like mental juggling for me. Just the act of organizing all of this stuff should count as a new task as well! :)

On a side note: Thank you for all of the hugs in Friday Harbor. I ran into so many people, whom I haven't seen in ages. It's a powerful thing, growing up in Friday Harbor. I appreciate the support, so much so that I can't even begin to explain it. Thanks you guys. I'm truly blessed. I had the chance to jog around town while I was there. It was extremely nostalgic. It's fun having little ghost like memories, so vivid. As a 12 year old, in line at the movie theater, with its' one showing. Walking past Islanders bank headed to the Elementary School for JV softball practice. Wandering around town with my friends because my mom frowned upon sitting on a bench (she wasn't keen on loitering, "It leads to trouble."). I remember walking the 1.5 miles to the drug store with Nicky, we each started with a few quarters but on the way home, it had magically transferred into one hundred Swedish fish.

Most of all, at the age of 17, I remember jogging along our dirt road to a neighbors private grassy landing strip for their Cessna (sounds swanky, but that's the island - it takes all types). I dropped down to the ground, and looked up to the sky. I knew that no one could see me, since the grass hadn't been mowed in months. It was a few feet tall, and the perfect disguise. I remember thinking, "There is a purpose for me. Something big." I knew that I wouldn't have a typical life (although, now I wonder what that definition even is). I remember that moment. It was pretty powerful. I don't know if this brain tumor is my purpose, but I'm incredibly grateful when I hear that my story helps people. Hearing that my story, or this blog, touches people in some way is extremely rewarding. It makes me feel like my journey is not only for me, but for others as well. Health is real. It's probably, the most important thing for every individual - for without it, your body ceases to exist. For those of you who are dealing with anything hard, I'm sorry. This is me hugging you.

Friday, December 17, 2010

A Surprise Package

The other day a surprise package arrived. It contained a gorgeous, soft, hand knitted scarf. There was sweet card, and no signature. No return address.

It was from a reader of my blog, whose name I don't know, whom I've never met.

Constantly, especially in my car as I listen to music, I think about how lucky I am. This tumor has been a lucky charm. I feel like my life is absolutely amazing. A hero by my side who constantly loves me through amazing changes, an unbelievable family who supports me in every single way, friends who always keep me laughing and hugging me when I need to cry, and the support from people whom I've never met, but love me as if we'd been friends for an eternity. I've been introduced to a whole new world because of this little nugget. I have the opportunity to share my life, and for the first true time, I feel like I actually have something important to talk about. This story, of my journey, is raw and honest. I'm sure I sometimes sound foolish, or ridiculous, but that's a part of who I am.

I'm so insanely grateful for all of the support. I have the best group of people cheering me on, keeping space for me in their heart. I couldn't ask for anything more.

I don't really have a solid opinion about lives being predestined. I don't exactly believe that everything happens for a reason. I do, however, believe that this tumor has brought the best out of me. This is a challenge, and I'm grateful to have the chance to share it with all of you.

Thank you for taking the time to read my blog, and a very, very special thank you to the unbelievably talented maker of the scarf. I'm humbled by the fact that you took the time to make a scarf just for me, "to keep me warm in those cold Wenatchee winters." I can't tell a lie, it made me cry with happy tears. I'm so truly grateful for all of your love and kindness. Thank you.

Photo of the scarf coming soon! :)

Thursday, December 16, 2010

Eagle Eyes

I have a confession to make...I cheated on my ketocal. Some friends threw Danny and I a small engagement party and there was so much delicious food and wine. I looked at Danny with big doe eyes and asked him if one night would kill me. Quite the manipulator don't you think!? The girls hosting the party had all kinds of foods that I could eat, so I didn't cheat THAT much, but I did down a couple of cupcakes and helped myself to a few glasses of wine. I felt guilty at first, with the initial bite, but in the morning I felt relieved. Who was I kidding that sugar would never again cross through my lips.

As I've mentioned before, I've never been great at doing things 100%. The stress of the diet and amount of restriction was overwhelming. I've since decided to keep with the diet normally, but if there's a special occasion I can indulge. I know it's my health we're talking about, but I'm also wanting to live my life.

On a side note, I just returned from the eye doctor. During my last speech therapy session, Julie noticed that I get closer and closer to the paper as I read, and she was concerned about my eye sight. When we were younger, Kaal and I would hunt for frogs, calling me, "Eagle Eyes." He thought that I had some sort of super human eye sight, but later we found out that Kaal badly needed glasses.

I have always wanted glasses - weird, I know. They're just so sophisticated.  I'm convinced that it's impossible to look unintelligent if you wear glasses. All of my wishing has fallen on deaf ears though. My eye sight is still perfectly fine. The eye doctor said that when kids are learning to read they often subconsciously get closer and closer to the page. Good to know! For the first time, as I left the eye doctor I was relieved instead of being disappointed. I recently don't have insurance for eye care, and I just avoided the extra expense of glasses and contacts. Practical Jess kicked in...I now can rest easy with one less doctor's appointment. Woo hoo!

Sunday, December 12, 2010

Welfare Cards vs Welfare Vouchers

I finished my argument paper today. Although there's no doubt in my mind this homework is extremely beneficial to me, I can't help but feel stupid sometimes while working on it. To have mental abilities and then lose them is heartbreaking and discouraging. I managed to avoid crying this time. I feel like that was a success.

This tumor is bittersweet. I'm learning invaluable lessons; so much about life, who I am, what I can handle, and what's important. At the same time, I feel like a simpleton. I honestly feel bad that I agreed with her critics and thought Jessica Simpson's nickname " Jessica Simpleton" was hilarious. Now the jokes on me. I never thought I'd feel that way. A lot can change very quickly can't it.

I'm not going to share my 1/2 page paper because I'm embarrassed but, for the record, my paper was written after reading the following NWPR article:

Wash. Welfare Cards Used At Out-Of-State Liquor Stores, Strip Clubs 
Posted: Friday, December 10, 2010

OLYMPIA, Wash. – Some Washington welfare recipients are withdrawing cash at out-of-state liquor stores, smoke shops and even strip clubs. That’s the finding of a public radio investigation into welfare debit card use outside Washington’s borders. The finding comes at a time when the state’s welfare program is 82-million dollars in the red. Olympia Correspondent Austin Jenkins reports.

The Safari Showclub bills itself as Portland’s finest Rock N Roll strip club. Manager Paul Le says there are plenty of ways to spend your hard earned cash.

Paul Le: “Tip the dancers, get lap dances, gamble, video poker.”

Need some cash? The Safari conveniently has an ATM machine on-site. And that’s where this September a Washington welfare debit card was used to withdraw money. Now there’s no proof that cash was actually spent inside the Safari Club. But manager Paul Le admits it doesn’t look good.

Paul Le: “I’m appalled that somebody would get state dollars to help them out and would spend that kind of money in that way. That money’s supposed to go to help them and their family.”

The Safari isn’t the only Portland strip club that shows up on a database I requested of out-of-state cash withdrawals by Washington welfare recipients. There transactions at Mystic Gentlemen’s Club. Soobies. Frolics. Docs Club 82. The Cabaret Lounge. And The Silverado, which features male exotic dancers. And it’s not just nude clubs. In the month of September, I found nearly a hundred questionable cash withdrawals: at liquor stores in California and Hawaii, Idaho smoke shops, Montana casinos, not to mention bars all over the country.

Thomas Shapely: “Speaking for myself as a taxpayer, yes, I think those things are inappropriate use.”

But Thomas Shapely, with Washington’s Department of Social and Health Services, says there’s no formal prohibition against using welfare cash on booze, cigarettes or even strippers. In fact he tells me state law only says you can’t use the money to gamble.

Austin Jenkins: “Does this agency think that there maybe there should be, if not additional state laws saying you can’t do this, you can’t do that, at least guidance to this user that this would be an appropriate use of the cash, this would be an inappropriate use of the cash?”

Thomas Shapeley: “I think that would be a fine idea. We’ve talked about it here about doing a little better public outreach.”

Shapley says it would be up to the legislature to go beyond the current ban on gambling with welfare dollars to include other no-nos. But Republican State Senator Joe Zarelli doesn’t think investigating these kinds of cases would pay in the end.

Joe Zarelli: “I think the better answer is to severely reduce as much as possible the amount of cash you’re putting in people’s pocket to use on things that we don’t want them to use.”

Zarelli advocates moving to a voucher system for Washington’s nearly 66-thousand welfare recipients.

Joe Zarelli: “For the necessities that that family needs, food, shelter, clothing, transportation.”

Robin Zukoski: “It’s tremendously expensive from an administrative point of view to run a voucher program.”

Robin Zukoski is an attorney who’s represented welfare families for thirty years. She thinks this issue is a distraction. Zukoski says welfare clients in strip clubs are not the reason Washington’s welfare system is $82M in the red. She says that’s because the economy has hammered families and the state budget and the program has experienced a thirty-percent growth in demand.

Robin Zukoski: “We’re asking low-income families to survive on a very small amount of money each month. For a family of three, it’s about $542. However they can we work that magic and live within the limited means that they have we should not be questioning or judging or second-guessing where they’re spending the money or where they’re getting the cash benefits.”

Washington’s Department of Social and Health Services does electronically monitor out-of-state welfare card use. But the focus is identifying people who have moved out-of-state but are still collecting Washington welfare benefits. In fact, in September the agency cut fifty-five of them from the program after determining they no longer reside in Washington.

Copyright 2010 Northwest News Network

Friday, December 10, 2010

Diamond Blackfan Anemia

I would like to apologize for being a huge baby. Just after the last post I thought about a friend from high school whose daughter has Diamond Blackfan Anemia. Mia, a seven year old, lives off of blood transfusions. She regularly has to get poked and prodded every 3-4 weeks. The most amazing thing about Mia is that she does it all with a smile, she's the cutest little curly head ever.

Here I am, a complete whiner, about such a trivial thing. An IV. Mia's big fear probably isn't the IV, it's having the blood to survive. During my last MRI, Danny went and donated blood just to feel close to me, even though technically he was across the entire hospital. Maybe THAT'S what I need to do, voluntarily get poked and donate my blood. I'm not sure if they'll take it. They might toss out brain tumor blood, but it's worth a shot to check it out.

I don't know why I was boo hooing. I'm embarrassed.

If you want to read Mia's story, and maybe donate to her website, please check it out:

Wednesday, December 8, 2010

Speech Therapy Success

I'm happy to report that Monday's speech therapy was an unbelievable success. For the first time I was able to answer all four of the reading comprehension questions correctly! Here's the trick, I need to slowly read the passage aloud twice. And when I mean slowly, I mean s-l-o-w-l-y. Who cares though, it's a start! Woo hoo!

For next week, I have ANOTHER position/argument paper. This will be #4. Luckily, they're never long, just about 2-3 of a page. Each time I have a paper, Julie (my speech therapist) helps me hone in on organizing my thoughts. She's teaching me to use organization techniques, which I know I learned in high school (like idea bubbles), it's not enough to remember how to do a technique, it's all figuring out how to implement them. That's the hard part. I have such a hard time reaching into my brain and finding thoughts. It's weird. I think this part of my recovery is going to take quite a while.

Last night, just as I was falling asleep I had a mini panic attack. I realized the MRI is on January 14th and I remembered how horrible the IV is. I usually end up quietly sobbing. I'm a pretty big ninny. They can never find my vein so they end up digging around in my arm forever, changing puncture locations and veins, then they change arms, and then change back to the original arm. It sucks. I wish I could say that I can shove the thoughts out of my mind, but I can't. I'm trying my best, but until I replace the thoughts with something positive (and I can't seem to find anything that feels quite right) I'm going to be mulling over this for a little bit.

Anyway, all in all, things are going really well. I have two more speech therapy appointments to go in this session. Then, soon, on January 14th I have my next MRI. I'm feeling pretty confident that I'm doing everything I can to recover and be healthy. I'm sleeping 9-10 hours a night, resting as much as possible. I'm hitting this diet with a vengeance. I have yet to cheat or eat anything off my list of foods. I'm maintaining the lower calorie restrictions, and I'm still alive and kickin'. I'm cranky though. Maybe in a few more weeks (it's only been a week and a half) I'll stop craving sourdough bread, homemade cookies, red wine, and all of my other favorites. Small portions have always been my enemy, I'm a lover of food and I tend to go big or go home. Now, I'm trying to fight my desire to eat more. It's EXTREMELY tough. The only saving grace has been the 12lb weight loss. But truthfully, I'd give up the 12lbs if I could eat whatever I wanted. Sadly, this isn't about what I want, it's about surviving. It's my only real long term goal.

Tuesday, December 7, 2010

From the first neurosurgeon's appointment at the UW I saw this painting. It always makes me smile. I remember thinking of it when I went in for the first surgery, I had walked past it after the surgery prep meeting. I focused on it when I was in recovery. When I was released, I admired it as Danny wheeled me to the car, and Jess Abu Dhabi carried all of the goodies that my friends and family brought me (thank you, thank you, thank you!). Now, every time I head to my speech therapist's office I spend a few minutes along the way looking it. I like to think that someday that'll be Danny and me.

According to the artist, the characters in the painting are not real people, they're bits and pieces of bodies and faces from his mind. It's a fictional event in the painting. I just read the side note yesterday, and I was surprised. I thought it was a real photo, or at least a painting of a photo or moment in time.

Anyway, I just wanted to share this painting with everyone because it gives me so much joy. Every time I see this painting I get the warm fuzzies, and I can't help but smile.

Sunday, December 5, 2010

Squeezing Mr Yuck

The first few days of this new keto cal diet, I thought I'd starve to death. Now, things are evening out. I've managed to keep up my 6 day a week workouts. I run for 30 minutes, and do as many man push ups as possible (averaging 20, depending on my level of exhaustion).

When I run, and I don't feel like pushing through, I imagine a Mr Yuck sticker between my index finger and thumb, and I squish it. I think about that little mean nugget in my brain that wasn't invited. Then, I imagine an evil, ridiculous laugh cross my lips. I know that I'm his food source, and that I'm in the power seat; he's hungry and I'm starving him. Sucker!


Before the diet I was 5'7 and 155 lbs
Currently, I'm 5'7 and 145 lbs

I'm starving that dirty little nuisance, and I'm healthier than ever. Shedding weight has never felt better. I have an enemy to fight, and although I respect the power that he has, I still want to win.

Saturday, December 4, 2010

KetoCal Diet & Malignant Brain Tumors

Recently, I came upon an extremely interesting study. It found that a restricted diet (with specific foods), slowed the growth of astrocytomas (my type of brain tumor) by up to 70% (also slowing gliomas by 35% +).

Basically, the diet limits absolutely everything, but focuses mostly on avoiding sugars, and simple carbohydrates (which turn into glucose in the body). Apparently, sugar and glucose feed brain tumor cells. Luckily, after reading the study, I now know a way to starve the tumor, and still feed my healthy brain cells. First off I have to restrict my daily caloric intake by 30-35%, while avoiding sugars and carbs. Basically, I'm trying to rid my body of the storage center that could be used as fuel for the tumor. Next, once I lose that extra storage, I maintain a variant of the keto-cal diet. This study is really important because it showed that healthy brain cells use ketones (sp?) as fuel while brain tumors use glucose. So, if I can limit my sugar intake and glucose storage, I can slow the growth of my brain tumor by an insane amount.

There's a ton of information in the study, and since reading it, Danny, my parents and I have been researching like crazy to make sure that we're not flying blind with one study. We were also worried about the health impacts of being on a keto-cal diet for the long term, but once we found a study by John Hopkins (which which coincidentally is the #1 brain tumor center in the nation) we felt pretty relieved. The keto-cal diet originated to treat children with epilepsy, and oddly this diet treats not only epilepsy, it is an effective treatment for malignant brain tumors. I'm so excited to have concrete information to grasp onto. I want to conquer this tumor and live an extremely long life. Hopefully, this new knowledge can help me do that. I'm willing to do whatever it takes, I just need concrete proof that I'm headed in the correct direction. Now, I feel like I have that. It's a pretty amazing feeling!

If you're interested in reading the original study, you can click here, otherwise you can read it below. It's pretty interesting stuff.

The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer

Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG).
Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal® was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal® on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet.
KetoCal® administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal® diet reduced plasma glucose levels while elevating plasma ketone body (β-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal® groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, β-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy.
The results indicate that KetoCal® has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal® for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal® is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.
Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children [1-4]. Many current therapies for malignant brain tumors are ineffective in providing long-term management because they focus on the defects of the tumor cells at the expense of the health and vitality of normal brain cells [5-7]. We previously showed that caloric restriction (CR) is anti-angiogenic, anti-inflammatory, and pro-apoptotic in the experimental mouse (CT-2A astrocytoma) and the human (U87-MG malignant glioma) brain tumors [8-11]. CR targets tumor cells by reducing circulating glucose levels and glycolysis, which tumor cells need for survival, and by elevating ketone bodies, which provide normal brain cells with an alternative fuel to glucose [5,9,11]. We previously used linear regression analysis to show that blood glucose levels could predict CT-2A growth as well as insulin-like growth factor 1 (IGF-1) levels, which influences tumor angiogenesis [8,9]. In contrast to glucose, ketone bodies (β-hydroxybutyrate and acetoacetate) bypass glycolysis and directly enter the mitochondria for oxidation [12,13]. By bypassing glycolysis, ketone bodies are also effective for treatment of inherited defects in glucose transporters and pyruvate dehydrogenase, which connects glycolysis with respiration [14-16]. Ketone bodies are more energetically efficient than either pyruvate or fatty acids because they have a greater hydrogen/carbon ratio (more reduced) than pyruvate and, unlike fatty acids, do not uncouple mitochondria [5,17]. The transition from glucose to ketone bodies for brain energy metabolism is best under the natural conditions of CR [5,8,18].
The metabolism of β-hydroxybutyrate (β-OHB), the major circulating ketone body, for energy depends on the expression of two key mitochondrial enzymes: β-hydroxybutyrate dehydrogenase (β-OHBDH), and succinyl-CoA: 3-ketoacid CoA transferase (SCOT) [13,19-21]. These enzymes become critical when neurons and glia transition to ketone bodies in order to maintain energy balance under conditions of reduced glucose availability. In addition to serving as a more efficient metabolic fuel than glucose, ketone bodies also possess anti-inflammatory potential through reduction of reactive oxygen species and increase of glutathione peroxidase activity [5,17,22]. Brain tumors, like most malignant tumors, are largely dependent on glucose and glycolysis for their growth and survival due to abnormalities in the number and function of their mitochondria [5,8,23-27]. The transition from glucose to ketone bodies as the primary energy source of the brain under calorically restricted conditions exploits the metabolic deficiencies of brain tumor cells while enhancing the health and vitality of normal neurons and glia according to principles of evolutionary biology and metabolic control theory [5,28].
Nebeling and co-workers previously found that a high fat/low carbohydrate ketogenic diet (KD), consisting of medium chain triglycerides, provided long-term management of pediatric astrocytoma while enhancing the nutritional status of the patients [29]. The findings in human pediatric astrocytoma were confirmed in the experimental mouse CT-2A astrocytoma using a lard-based rodent ketogenic diet [8,9]. CR and some KDs, however, are not standardized diets and may be difficult to implement in the clinic due to issues of compliance. For example, CR in mice mimics therapeutic fasting in humans, involving water-only dieting, whereas medium chain triglyceride or lard-based ketogenic diets can cause gastrointestinal and kidney problems in both children and adults [30-33]. Our goal was to develop a more effective alternative diet therapy for brain cancer that could extend survival without compromising the health and vitality of normal cells.
In this study we evaluated the therapeutic efficacy of KetoCal®, a new nutritionally balanced soybean oil ketogenic diet that was formulated specifically for managing refractory epilepsy in children [34]. No prior studies have evaluated the therapeutic efficacy of KetoCal® for brain cancer management. Here we show that KetoCal®, given in calorically restricted amounts significantly reduced circulating plasma glucose levels while significantly elevating ketone body levels in mice bearing orthotopic CT-2A and U87-MG brain tumors. Moreover, the restricted KetoCal® diet reduced brain tumor growth and microvessel density, while extending mouse survival. Gene expression for β-OHBDH and SCOT was lower in the tumors than in contralateral normal brain suggesting that the brain tumors have reduced ability to metabolize ketone bodies for energy. This preclinical study indicates that KetoCal® is a safe and effective diet therapy for malignant brain cancer and can be considered as an alternative or adjuvant therapeutic option. A preliminary report on this work has appeared [35].
Mice of the C57BL/6J (B6) strain and the BALBc/J-severe combined immunodeficiency (SCID) strain were obtained from the Jackson Laboratory, Bar Harbor, ME. The mice were propagated in the animal care facility of the Department of Biology, Boston College, using animal husbandry conditions described previously [36]. Male mice (10–12 weeks of age) were used for the studies and were provided with food under either restricted or unrestricted conditions (as below). Water was provided ad libitum to all mice. The SCID mice were maintained in laminar flow hoods in a pathogen free environment. All animal experiments were carried out with ethical committee approval in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care Committee.
Brain tumor models
The syngeneic mouse brain tumor CT-2A, was originally produced by implantation of a chemical carcinogen, 20-methylcholanthrene, into the cerebral cortex of B6 mice and was characterized as an anaplastic astrocytoma [37,38]. The morphological, biochemical, and growth characteristics of the CT-2A mouse brain tumor were previously described [37,39-42]. The U87-MG (U87) tumor was originally derived from a human malignant glioma cell line and was grown as a xenograft in the SCID mice [43,44].
Intracerebral and subcutaneous tumor implantation
The mouse CT-2A and human U87 tumors were implanted into the cerebral cortex of the B6 or SCID mice, respectively, using a trocar as we previously described [41]. Briefly, mice were anesthetized with 2,2,2-tribromoethanol (Sigma Aldrich, St. Louis, MO) given intra-peritoneally and their heads were shaved and swabbed with 70% ethyl alcohol under sterile conditions. Small tumor pieces (about 1 mm3) from donor mice were implanted into the right cerebral hemisphere of anesthetized recipient mice as we recently described [41]. Initiation of tumors from intact tumor pieces is preferable to initiation from cultured cells, since the tumor tissue contains an already established microenvironment that facilitates rapid tumor growth [41]. All of the mice recovered from the surgical procedure and were returned to their cages when they appeared fully active.
For the survival studies, CT-2A or U87 flank-grown tumors were removed from B6 or SCID mice, respectively, and were rinsed and diced in cold phosphate-buffered saline (PBS) at pH 7.4. Mice were anesthetized with isoflurane (Halocarbon, NJ) and 0.1 ml of diced tumor tissue, suspended in 0.2 ml PBS, was implanted subcutaneously (s.c.) in the right flank by injection using a 1 cc tuberculin syringe and 18-gauge needle. The flanks of recipient mice were shaved in order to facilitate tumor detection and growth assessment. The inoculated mice were monitored daily for nodule formation.
Diets and feeding
The mice were group housed prior to the initiation of the experiment and were then individually housed in plastic shoebox cages one day before tumor implantation. All mice received PROLAB chow (Agway Inc., NY) prior to the experiment. This is a standard high carbohydrate mouse chow diet (SD) and contains a balance of mouse nutritional ingredients. According to the manufacturers specification, this diet delivers 4.4 Kcal/g gross energy, where fat, carbohydrate, protein, and fiber comprised 55 g, 520 g, 225 g, and 45 g/Kg of the diet, respectively. The KetoCal® ketogenic diet was obtained as a gift from Nutricia North America (Rockville, MD, formally SHS International, Inc.). KetoCal® is a nutritionally complete ketogenic formula and, according to the manufacturers specification, delivers 7.2 Kcal/g gross energy where fat, carbohydrate, protein, and fiber comprised 720 g, 30 g, 150 g, and 0 g/Kg of the diet, respectively. There are also minor differences between the two diets for the content (g/kg of diet) of amino acids, vitamins, minerals and trace elements. The diet has a ketogenic ratio (fats: proteins + carbohydrates) of 4:1 and the fat was derived from soybean-oil. The KetoCal® diet was fed to the mice in paste form (water: KetoCal®; 1:2) within the cage using procedures as we previously described [18]. A comparison of the nutritional composition of the SD and the KetoCal® diet is presented in Table 1.
Table 1
Table 1
Composition (%) of the Standard Diet and the KetoCal® Ketogenic dieta
The animal room was maintained at 22 ± 1°C, and cotton nesting pads were provided for additional warmth. All intracerebral (i.c.) tumor-bearing B6 and SCID mice were maintained on the SD for three days following tumor implantation (day 0, Figure Figure1)1) and were then randomly assigned (arrow, Figure Figure1)1) to one of three diet groups that received either: 1) the standard diet fed ad libitum, or unrestricted (SD-UR), 2) the KetoCal® diet fed ad libitum, or unrestricted (KC-UR), 3) the KC diet restricted to reduce body weight by approximately 20% of the original body weight at day 3 (KC-R). The dietary treatments were continued for 8 days for tumor weight analysis. For the survival analysis, the dietary treatment was initiated 7 days after subcutaneous implantation and continued until the tumors reached 2.5 cm3.
Figure 1
Figure 1
Influence of diet on body weight in B6 mice bearing the mouse CT-2A astrocytoma (A), and in SCID mice bearing the human U87 glioma (B). Tumors were implanted orthotopically at day 0, and diets were initiated at day 3 (arrow). The SD-UR, KC-UR, and KC-R (more ...)
Tumor growth and survival analysis
Intracerebral tumor growth was analyzed directly by measuring total tumor wet weight. Tumors were dissected from normal appearing brain tissue and were weighed. Survival was determined as the time for subcutaneous tumors to reach the size of 2.5 cm3 after tumor inoculation as previously described [45]. Calipers were used to measure tumor volume as previously described [46]. Tumor nodules appeared approximately 7 days following inoculation.
Measurement of plasma glucose and β-hydroxybutyrate (β-OHB)
Blood was collected from mice on the last day of the experiment (between 1–4 pm) and before sacrifice and tumor resection. All mice were fasted for 2 hours before blood collection to stabilize blood glucose levels. The mice were anesthetized with isoflurane (Halocarbon, NJ), and the blood was collected from the heart into heparinized tubes. The blood was centrifuged at 1,500 × g for 10 min, and the plasma was collected and stored at -80°C until assayed. Plasma glucose and β-OHB concentrations were measured spectrophotometrically using the StanBio® Enzymatic Glucose Assay (1075-102) (StanBio Laboratory, Boerne, TX, USA) and a modification of the Williamson et al., enzymatic procedure [47], respectively. For blood ketone body analysis, we measured only β-OHB levels because this is the major blood ketone body in plasma [48,49].
Tumor samples were fixed in 10% neutral buffered formalin (Sigma, St. Louis, MO) and embedded in paraffin. Tumors were sectioned and examined by light microscopy. For the histological studies, treatment was initiated as described above and was continued for 7 days to prevent tumor-associated tissue distortion.
Factor VIII Staining and Microvessel Analysis
Tumor sections were incubated with trypsin at 37°C for 30 min after deparaffinization, rehydration, and washing as we described recently [10,11]. Briefly, the sections were quenched with 0.3% H2O2-methanol for 30 min and then blocked with 10% normal goat serum in phosphate buffer plus albumin (PBA) that contained 100 ml of 0.01 M phosphate and 0.9% sodium chloride (pH 7.4) with 1.0 g of bovine serum albumin and 0.1 ml of Tween 20. The sections were treated with rabbit polyclonal antibody directed against human factor VIII-related antigen (Dako Corp., Carpinteria, CA; 1:100 dilution with PBA) followed by a biotinylated anti-rabbit IgG at 1:100 dilution (Vector Laboratories, Inc., Burlingame, CA). The sections were then treated with avidin-biotin complex followed by 3,3'-diaminobenzidine as substrate for staining according to the manufacturers directions (Vectastain Elite ABC kit; Vector Laboratories, Inc.). The sections were then rinsed three times with 0.01 M phosphate buffer with 0.9% NaCl. Sections were counterstained with methyl green and mounted. Corresponding tissue sections without primary antibody served as negative controls. Microvessel density was quantified by examining areas of vascular hot spots in high power fields (hpf, 200 ×) as previously described [50] with some modifications [51]. Briefly, sections were scanned at 40 × and at 100 × for the localization of vascular hot spots. Blood vessels were counted at 200 × in the three most non-necrotic vascular areas of the tumor. The values of the three sections were averaged for each CT-2A tumor. Branching structures were counted as a single vessel as described previously [50]. Blood vessels were not counted in the U87 tumor due to extensive hot spot areas. In this case, only the tumor sections were shown for qualitative analysis.
Semi-quantitative RT-PCR
Total RNA was isolated from homogenized tissue using TRIzol Reagent (Invitrogen, La Jolla, CA), following the manufacturers protocol. Spectrophotometric measurements at 260 and 280 nm determined RNA concentration and purity. Single-strand cDNA was synthesized from total RNA (3 μg) by using oligo (dT) primers (Promega, Madison, WI) in a 20-μl reaction with Moloney murine leukemia virus reverse transcriptase (M-MLV RT; Promega) according to the manufacturers protocol. cDNA (3 μl) was used for PCR amplification of specific regions of the β-OHBDH, SCOT, and β-actin genes. Primer sequences and amplicon information for the mouse and the human β-actin, β-OHBDH, and SCOT genes can be viewed at NCBI (National Center for Biotechnology Information, PubMed) using the accession numbers EF095208-EF095213. Gradient PCR was performed to obtain optimal primer annealing temperatures as previously described [52]. In order to determine the optimal linear range for semi-quantitative RT-PCR, PCR was performed at increasing cycle numbers. PCR amplification was performed with Taq DNA polymerase (Promega) using similar protocols for each gene. PCR products (10 μl) were separated on 1.0 % agarose gels containing ethidium bromide, visualized with UV light, and analyzed using 1D Kodak Software (Eastman Kodak Co., Rochester, NY).
Statistical analysis
The one-way analysis of variance (ANOVA) was used to analyze body weight, tumor growth, plasma glucose, and β-OHB levels [53]. The Fishers PLSD test was used to calculate two-sided pair-wise comparison among different test groups by use of Statview 5.0. In each figure, n designates the number of individual mice analyzed. Error bars in the figures are expressed as mean ± SEM. Survival was computed and plotted according to the nonparametric Kaplan-Meier analysis, and comparison of control and treated groups was made using the log-rank test [53].
The objective of this study was to determine if the KetoCal® ketogenic diet could be therapeutic against experimental mouse and human brain tumors when administered in restricted amounts according to recommendations for treatment of children with refractory epilepsy. In contrast to other ketogenic diet formulations (lard-based or medium chain triglyceride diets), which are not standardized or commercially available, KetoCal® is a nutritionally complete medical food for children that would be widely available for alternative indications such as malignant brain cancer. Because we previously showed that CR of the high carbohydrate standard diet has anti-tumor and anti-angiogenic effects against the CT-2A and U87 experimental brain tumors [10,11], we did not include a hypocaloric group for the high carbohydrate diet in this study. Consequently, the restricted KetoCal® mouse groups were compared to mouse groups receiving either the standard chow diet or the KetoCal® diet in unrestricted amounts.
Body weight and diet tolerance
Body weights remained similar in the unrestricted standard diet fed group (SD-UR) and in the unrestricted KetoCal® diet fed group (KC-UR) throughout the study despite major differences in the caloric content and composition of the diets (Table 1 and Figure Figure1A1A and and1B).1B). 
The restriction of KetoCal® in the KC-R group was according to the manufacturers recommendation for the management of childhood epilepsy (Nutricia North America). This involved administration of 65–70% recommended daily allowance of calories or an approximate 30–35% calorie restriction. This degree of dietary restriction gradually produced an approximate 20–23% body weight reduction by 11 days post i.c. tumor implantation in the B6 and SCID KC-R groups. No signs of vitamin or mineral deficiency were observed in the KC-R mice based on standard criteria in mice [54]. Indeed, physical activity and grooming behavior was noticeably greater in the KC-R groups than in the SD-UR and KC-UR groups. These findings indicate that KetoCal® was well tolerated in tumor-bearing B6 and SCID mice and, when given in restricted amounts, produced noticeable improvement in health and vitality.
Influence of diet on tumor growth and mouse survival
Intracerebral growth of the CT-2A and U87 tumors was rapid in both the SD-UR and KC-UR groups, but growth was reduced by approximately 65% and 35% in the KC-R groups, respectively (Figure (Figure2A2A and and2B).2B). These reductions in tumor weight exceeded the reductions in body weight. It is important to mention that all implanted CT-2A and U87 tumors grew in the KC-R groups, indicating that restricted feeding did not prevent tumor "take" but significantly reduced the intracerebral growth rate. Survival, assessed as the time required for subcutaneous tumor nodules to reach 2.5 cm3, was significantly longer in the KC-R groups than in the SD-UR or KC-UR groups (Figure (Figure3A3A and and3B).3B). No significant differences in survival were found among tumor-bearing mice in the SD-UR or the KC-UR groups. These findings indicate that KetoCal®, administered in recommended restricted amounts, significantly reduced tumor growth and extended survival in mice bearing either the mouse CT-2A or human U87 brain tumors.
Figure 2
Figure 2
Influence of diet on the intracerebral growth of the CT-2A (A) and the U87 (B) brain tumors. The asterisks indicate that the tumor weights of the KC-R groups differed from those of the SD-UR groups at the P < 0.03 *, and the P < 0.01 ** (more ...)
Figure 3
Figure 3
Influence of diet on the percentage of mice with the CT-2A (A) or the U87 (B) brain tumors < 2.5 cm3 in size. Data are expressed as Kaplan-Meier survival curves. Survival was significantly longer in the mice on KC-R diet (▴) than on either (more ...)
Influence of diet on plasma glucose and β-OHB levels
A transition from glucose to ketone bodies for energy under caloricaly restricted conditions is known to inhibit brain tumor growth through multiple integrated systems [5,9-11]. Plasma glucose levels were significantly lower in the KC-R mouse groups than in the SD-UR or the KC-UR groups (Figure (Figure4A4A and and4B).4B). Plasma glucose levels, however, were similarly high in both UR-fed mouse groups. These findings are consistent with our previous studies in mice showing that the KD does not lower plasma glucose levels when administered in unrestricted amounts [8,18]. In contrast to glucose levels, circulating β-OHB levels were 2 to 3-fold greater in the KC-UR groups than in the SD-UR groups (Figure (Figure4C4C and and4D).4D). Interestingly, β-OHB levels were 5 to 9-fold greater in the KC-R groups than in the SD-UR groups. These findings are also consistent with our previous studies in mice showing that circulating β-OHB levels are greater under restricted than unrestricted dietary conditions [8,18,55,56].
Figure 4
Figure 4
Influence of diet on plasma glucose and β-OHB levels in B6 mice bearing the CT-2A astrocytoma (A and C), or in SCID mice bearing the human U87 glioma (B and D). Values are expressed as mean ± SEM (n = 12–14 mice per group) and (more ...)
Influence of diet on brain tumor vascularity
To determine if KetoCal® influenced angiogenesis, we used Factor VIII immunostaining to examine blood vessel densities in the CT-2A and U87 brain tumors. Three independent CT-2A and U87 tumors were chosen at random from each dietary group. The number of blood vessels in the CT-2A tumor was noticeably less in the KC-R group than in the SD-UR group (Figure (Figure5A).5A). Also, CT-2A microvessel density/high power field was significantly less in the KC-R group than in the SD-UR group (Figure (Figure5B).5B). As found in the CT-2A tumor, the number of blood vessels in the U87 tumor was noticeably less in the KC-R group than in the SD-UR group (Figure (Figure5C).5C). Due to the high density of blood vessels in the U87 tumor compared to the CT-2A tumor, it was not possible to accurately measure microvessel density/hpf in the U87 tumor. No differences in the number or density of blood vessels were observed between the SD-UR and KC-UR groups for either tumor (data not shown). These findings indicate that KetoCal®, administered in restricted amounts, was anti-angiogenic in the CT-2A and U87 brain tumors.
Figure 5
Figure 5
Influence of diet on vascularity in the CT-2A (A and B) and the U87 (C) brain tumors grown orthotopically in B6 or SCID mice, respectively. Vessels were stained with the Factor VIII antibody and each stained section was representative of the entire tumor. (more ...)
Differential mRNA expression for β-hydroxybutyrate dehydrogenase (β-OHBDH) and succinyl-CoA: 3-ketoacid CoA transferase (SCOT) in normal brain and in brain tumor tissue
β-OHBDH and SCOT are required for the metabolism of ketone bodies for energy in brain mitochondria [13,20,21]. We used semi-quantitative RT-PCR to compare β-OHBDH and SCOT mRNA levels in the CT-2A and U87 tumor tissue grown in the right cerebral hemisphere with those levels in the normal appearing brain tissue of the contralateral left hemisphere (Figure (Figure6A6A and and6B).6B). β-OHBDH and SCOT mRNA levels were significantly lower in the CT-2A and the U87 tumor tissue than in the normal appearing contralateral brain tissue. No differences in β-OHBDH and SCOT mRNA levels were found between normal appearing brain tissue from tumor-bearing mice and brain tissue from non-tumor-bearing mice (data not shown). These findings suggest that the CT-2A and the U87 tumor cells are less capable than the normal mouse brain cells in using ketone bodies for energy.
Figure 6
Figure 6
Expression of β-OHBDH and SCOT in B6 and SCID mouse brains and in CT-2A and U87 brain tumors. (A) RT-PCR was used to detect mRNA levels of β-OHBDH, SCOT, and β-actin as described in methods. Expression was evaluated in normal appearing (more ...)
We found that KetoCal®, a nutritionally balanced and commercially available ketogenic diet for children with epilepsy, significantly reduced the orthotopic growth and the vascularity of the mouse astrocytoma (CT-2A) and the human glioma (U87). Moreover, KetoCal® significantly prolonged survival in the tumor-bearing mice. It is important to mention that the anti-angiogenic and growth inhibitory effects of KetoCal® were observed only when the diet was administered in restricted amounts but were not seen when the diet was administered ad libitum, or in unrestricted amounts. These findings support previous observations that restriction of dietary calories has powerful anti-angiogenic and anti-inflammatory effects against cancer, including brain cancer [9-11,51,57,58]. Reduced caloric content lowers circulating glucose levels as we found in this study and in our previous studies [10,11]. Indeed, tumor growth is more strongly correlated with circulating glucose levels than with circulating ketone body levels [8]. The reduction in glucose levels following restriction of dietary calories largely accounts for why tumors grow minimally on either restricted ketogenic diets or on restricted high carbohydrate standard diets. Restriction of calories in humans may be difficult to achieve, however, due to issues of compliance. Compliance may be better with KetoCal® as this diet was designed for managing refractory human epilepsy under calorically restricted conditions. CR, however, is not directly comparable in mice and humans. For example, a 40% CR diet in mice is comparable to therapeutic fasting in humans, which can be difficult for many people [30]. In addition to reducing circulating glucose levels, a restriction of total calories also reduces potential adverse effects of the high fat content of the diet since energy homeostasis is maximized under CR regardless of caloric origin [8,30]. The restricted KetoCal® diet should therefore be easier to implement than therapeutic fasting for brain cancer patients.
Although we previously showed that CR of a high carbohydrate standard diet or of a rodent ketogenic diet similarly reduce blood glucose levels, which tumor cells depend upon for survival [10,11], our findings in this study showed that administration of KetoCal® under restricted conditions was more effective in elevating circulating ketone bodies than was administration under unrestricted conditions. This is important since mild ketosis, under conditions of reduced glucose availability, is essential for enhancing the bioenergetic potential of normal brain cells [5,17,18]. Additionally, ketone bodies may directly protect normal neurons and glia from damage associated with aggressive tumor growth through a variety of neuroprotective mechanisms [59-64]. In contrast to most conventional brain tumor therapies, which indiscriminately target both normal cells and tumor cells, CR and particularly restricted ketogenic diets such as KetoCal® are the only known therapies that can target brain tumor cells while enhancing the health and vitality of normal brain cells [5,29]. In this regard, the calorically restricted ketogenic diet for brain cancer management stands apart from all conventional therapeutic approaches.
Previous studies indicate that many tumors including brain tumors are largely unable to metabolize ketone bodies for energy due to various deficiencies in one or both of the key mitochondrial enzymes, β-OHBDH and SCOT [19,21,65-68]. Our gene expression results in the mouse CT-2A and the human U87 brain tumors are consistent with these previous findings in other tumors and also support the mitochondrial defect theory of cancer [5,23,24,69]. The deficiencies in these enzymes, however, are important for tumor management only under calorically restricted conditions when glucose levels are reduced and when cells would require ketone bodies for energy. This is most evident from the analysis of tumor growth in the unrestricted KetoCal® groups where growth was rapid despite mild ketosis. This is attributed to the maintenance of high glucose levels, which the tumor cells will use for energy in preference to ketone bodies due to their dependency on glycolysis. However, when glucose becomes limited, as occurs under CR, the SCOT and β-OHBDH deficiencies would prevent tumor cells from using ketones as an alternative fuel thus metabolically isolating the tumor cells from the normal cells. We suggest that the genes for these enzymes could be useful markers for screening brain tumors and other tumor types that may be responsive to therapy using restricted KetoCal® or other restricted ketogenic diets. Further studies will be necessary to test this interesting possibility.
Long-term management of malignant brain cancer has been difficult in both children and adults. This has been due in large part to the unique anatomical and metabolic environment of the brain that prevents the large-scale resection of tumor tissue and impedes the delivery of chemotherapeutic drugs. Further, significant neurological abnormalities are often observed in long-term brain tumor survivors [70-72]. In light of the differences in energy metabolism between normal brain cells and brain tumor cells, we recently proposed an alternative approach to brain cancer management based on principles of evolutionary biology and metabolic control theory [5]. Specifically, the genomic and metabolic flexibility of normal cells, which evolved to survive under physiological extremes, can be used to target indirectly the genetically defective and less fit tumor cells. The results of this study using restricted KetoCal® as a therapy for experimental brain cancer provide direct support for this alternative approach to brain cancer management. It should be recognized that this alternative therapeutic approach may not be restricted only to brain cancer, but could also be effective for any cancer types containing genetically compromised and metabolically challenged tumor cells. Moreover, KetoCal® will be more effective in managing brain tumors in humans than in managing brain tumors in mice since prolonged caloric restriction can be tolerated better in humans than in mice due to intrinsic differences in basal metabolic rate [30].
Although Nebeling and co-workers were successful in managing childhood astrocytoma with a medium-chain triglyceride ketogenic diet [29,73], this KD formulation can be difficult to implement, is not standardized, and can produce some adverse effects as previously observed in children taking the diet for epilepsy management [32-34]. It is noteworthy that the children treated in the Nebeling study also expressed reduced blood glucose levels [29]. When administered in restricted amounts, KetoCal® may have greater therapeutic efficacy with fewer side effects than medium-chain triglyceride or lard-based KDs. Additionally, KetoCal® would eliminate or reduce the need for antiepileptic drugs for brain tumor patients since KetoCal® was designed originally to manage refractory epileptic seizures. Adjuvant steroidal medications, which are often prescribed to brain tumor patients and which can produce severe adverse effects, might also be reduced under the restricted KetoCal® diet since glucocorticoid levels increase naturally under calorically restricted conditions [74-76]. Ketogenic diets and calorically restricted diets can also antagonize cancer cachexia [9,11,77]. These observations, considered together with the anti-angiogenic effects of the diet, suggest that the restricted KetoCal® diet can manage brain tumors through multiple integrated systems.
Guidelines for the implementation of KetoCal® and other calorie restricted KDs in younger and older patients have been described previously [5,29,34,73]. KetoCal® could be administered to patients with brain tumors at medical centers or clinics currently using the ketogenic diet for managing epilepsy. Based on our findings in mice and those of Nebeling and co-workers in humans, initiation of randomized clinical trials are warranted to determine whether KetoCal® is effective for the long-term management of malignant brain cancer and possibly other glycolysis dependent cancers [78]. This is especially pertinent to patients with glioblastoma multiforme, an aggressive brain tumor type for which few effective therapeutic options are available. While KetoCal® was formulated for managing childhood seizures, it is likely that new KD formulations can be designed with nutritional and caloric compositions more appropriate for managing brain tumors [5,78]. This could also involve the use of low glycemic diets, which are effective in maintaining low circulating glucose levels and are easier to implement than some ketogenic diets [79,80]. Additionally, the diets could be combined with specific drugs to further enhance therapeutic efficacy. As a cautionary note, the calorically restricted KD would not be recommended for those few individuals with fasting intolerance due to defects, either inherited or drug-induced, in carnitine or fatty acid metabolism [49]. Our results in mouse and human brain tumor models suggest that the restricted KetoCal® diet will be an effective alternative therapy for managing malignant brain cancer in humans and should be considered as either a first line or adjuvant therapeutic option.
The results indicate that KetoCal® administered in restricted amounts has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors. Furthermore, genes for ketone body metabolism will be useful for screening brain tumors that could be targeted with KetoCal® or other calorically restricted high fat low carbohydrate diets. This preclinical study in mice indicates that the restricted KetoCal® diet should be an effective alternative therapeutic option for managing malignant brain cancer in humans.
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