Saturday, August 1, 2020

Traveling

After exactly six months, I went back to the airport on the day I started writing this post.  I didn’t get very far.  Business travel hasn’t really picked up again, and I didn’t have a flight to catch.  All conferences and workshops I was scheduled to attend since January have been canceled, postponed or moved online.  There doesn’t seem to be any change in the air.  I want to go to Japan and China this year, but I’m not really hopeful.  I can’t yet say what my first business trip after the start of the pandemic will be.

Last Friday, after having my pump removed at the hospital, I went to the airport solely to pick up a car for our summer vacation in Italy.  After much dithering, we had decided on Venice, or almost.  We had booked a week in a canvas cabin at a campground on one of the peninsulas that form the Venice lagoon and protect the city from the waters.  The campground had spots available less than two weeks before our departure – and, in the midst of summer, turned out to be less than half full.  The ferry to Piazza San Marcos was a five minute’s drive away.


Taken from Openstreetmap.org.

Calling where we stayed a campground is not exactly telling the whole truth.  If you’re thinking tents and communal washing rooms with cold showers, you’re way off.  I would describe the place as an upscale campground-themed holiday resort.  There were a few campsites and places for caravans, but most people stayed in cabins.  The restaurant served excellent pizza, much better than the restaurant just outside.  There was a beautifully tiled pool area with water slides, a spa area, a pool for babies and one for swimming.  The water was of the exact temperature to be refreshing but allow one to stay inside for hours without getting cold.  It was like magic.  At all hours of the day, activities for children took place.  There was a café, a pool bar and even a fitness club.  A fitness club on a campground!  A sandy beach gently easing into the warm waters of the Adriatic was a few steps away.  The children loved it – but they got the wrong idea of what a campground is.

Coronavirus has turned the world into a different place.  A half-empty campground in high season is only one aspect of it.  The world has also become much less diverse and more separated.  People prefer to stick to home (like the Swiss) or are forced to.  These days, most tourists in Venice are German.  Gone are the Americans, the Russians and the Chinese.  Instead, there were a lot of Italians.  Most are probably (re)discovering a city they have never or only very rarely visited because it was completely overrun and almost impossible to enjoy.

I first saw Venice more than 25 years ago.  It was one of the first trips I took with my dad after the wall had fallen.  We stayed in a hotel on the mainland and spent a few days exploring Venice.  The only thing I remember is a stash of black-and-white photos my dad took.  They’re now at my mom’s.  I haven’t had the chance to look at them again, but I think there were very few people in them.  Venice was peaceful back then.

When we disembarked our ferry, I was somewhere between surprised and shocked.  There were a lot of people.  This was a question of perspective.  Photos of Venice from last year show crowds shoulder to shoulder.  I read somewhere that it was impossible to stop when walking around.  People would just push you on.  Now, there were tourists on the Piazza San Marco and around the Rialto Bridge, but not too many.  Away from the main attractions, it was quiet.  Many alleys and even some of the squares were ghostly.  It was a beautiful experience.

For those in a tight covenant with their guilt, this might bring sleepless nights.  Is it right to enjoy blissful days by the sea when a virus is ravaging the world?  It is right to enjoy places that would be much more crowded and thus less enjoyable were it not for the virus?  Are we taking advantage of the virus?  I’m not given to guilt and see no need to apologize.  We had a great time, far from our ordinary life.  Tomorrow night, things go back to normal for me.  I’ll stop eating for four days once again.

Wednesday, July 22, 2020

Low spirits

Another two weeks have passed.  I’m back in the hospital for the fourth chemo session.  When this week is over, the first third of my second treatment program is history.  I have no idea how it is going.

I’m doing well.  I can’t complain.  I still don’t suffer side effects.  Over the course of the last two weeks, there was nothing to report out of the ordinary, which is one reason why I didn’t blog once.  Another reason is that I didn’t read anything interesting.  The third reason was the hot phase of birthday season.  Oma was in town to celebrate the birthdays of the boy and the boy’s father and, quite spectacularly, her own.  It was a busy week, with lots of activities, laughter, excitement and noise.

Throughout, I felt normal, happy, healthy.  With Oma, I hiked through the snow to a lunch spot at 12’000 feet, a glacier under my feet.  Family time was intense, especially when my sister made an unexpected appearance with her family over the weekend, but it was also good.  We don’t do this often enough.  I have no way of telling how I’m doing beneath all this, inside.

Is the therapy effective?  Is it pushing the cancer back?  Without side effects, it’s easy to think that the therapy doesn’t do anything positive either.  A clinical trial where I made the placebo group wouldn’t feel much different.  But I’m also fasting, and there I see clear effects.  Something is happening inside me.  I’m optimistic enough enough to be sure that I’m beating the cancer.

It is curious how my body has adapted to the fasting.  The second day used to be hard.  I couldn’t think of anything besides food.  I wasn’t hungry but suffered constant cravings.  It wasn’t pretty.  Now the second day is just like the first.  I slowly lose energy but that’s easy to accept.  It’s harder to keep the exhaustion from turning into surrender.  It’s a small step.  It would be so easy and so satisfying to just break the fast.  Sometimes I wonder whether, to put it overly dramatic, giving up a week of life each month is worth it.  There are no guarantees.

Another thing that bothers me about fasting is that I get rather irritable and obnoxious by the end of the second day.  I cease to be a pleasant person to be around.  The children deal with this in their lovely innocent way.  They just make more efforts to make me happy and show me their love.  For Flucha, who is also exhausted after work and housework or after dealing with the children all day, it’s more difficult.  She is almost as stubborn as me.  We end up having fights where we shouldn’t.  This drags my spirits down.  I want to eat again and go back to being the person I know.  This is not always the person I would like to be, but immeasurably better than the fasting caricature of myself.

Overall – and no matter how Flucha suffers from it – these are minor issues.  I also have problems with the solidity of my excretions.  Subsisting on water does that to you.  Again, this is not a big deal.  It resolves itself when I start eating again.  What really matters is that I’m beating this cancer.  For this, I’ll do and endure anything.

Wednesday, July 8, 2020

Five and three

Today was my third chemo session of the second round.  It was and still is surrounded by my fifth fasting period.  Almost everything went as before.  I continue to experience no side effects.  The nurses give me three pills to swallow at the beginning of the therapy and then an injection before they give me irinotecan.  It would be interesting to see how things go without those pills and the injection, but as they go well with them, I see no point in challenging the regime.  Fasting is said to help mitigate the side effects, but I don’t want to explore if it’s enough to replace the pills and the injection.

Fasting is easy.  It’s like not fasting, except you don’t eat.  Fasting is entirely passive.  There’s nothing to do.  I just don’t eat and wait for the period to end.  It also gets easier with time.  This time around I don’t have burning cravings for food.  I’m exhausted and feeble, but I don’t suffer.  When I first tried fasting, the second day was a mighty struggle.  It was tempting to quit.  Now I’m almost cruising through, though it is certainly not pleasant.

I am looking forward to breaking the fast each time.  Fasting and the desire to break it have a curious upshot.  The chemotherapy sessions have become something to look forward to.  Chemo allows me to lie on a bed for five hours with absolutely nothing to do.  It’s relaxing.  I tend to sleep.  There’s nothing negative to it.  Even the atropine injection doesn’t scare me.  And the end of the therapy at the hospital, when I go home with the bottle of fluorouracil, marks the beginning of the last 24 hours of fasting.  This fills me with joy.  As strange as it sounds, chemotherapy has become the highlight of my week.

I like to eat, but eating has become difficult for me.  I’m trying to square several conflicting objectives.  I need to regain the weight I lost during fasting.  I need to eat healthily, though maybe that’s the least of my worries at the moment.  Heart disease and diabetes wouldn’t be high up on my list of worries if I kept one.  And I need to starve the tumor of energy it can use and of growth factors.  How to get the balance right?

The solution I’ve come up with is threefold.

  • I consume lots of fat.  It took me a while to dial this in, but I think I’m getting there now.  There’s good fat and bad fat.  Bad fat, essentially trans fatty acids, should be avoided.  They are in fries and industrially-produced baked goods.  I don’t eat much of either.  Good fat comes from vegetable oils.  Drenching your food in oil is a good idea if you want to gain weight.  Olive oil is great, but adds a strong flavor that doesn’t always work.  I’ve come to like rape seed oil for its milder taste, and I appreciate that it’s probably healthier than butter.  Strange that I would suddenly construct my diet based on what’s healthy instead of what tastes good, but these are the days.
  • Protein is good.  When I come back from a bicycle ride, especially one that involved climbs, I consume a big protein shake.  Out of my enthusiasm for fat described above, I mixed the shake with heavy cream instead of milk the other day.  Not a good idea.  The mix quickly became sort of solid in the blender.  I could spoon it out, but it wasn’t what I had expected.  Meat also gives lots of protein, and it tastes good.  I have already substantially increased my meat consumption.  It’s now a race between me and the world.  Who’s going to die first?
  • Carbohydrates are ambiguous.  They are necessary for brain function and generally the primary source of energy.  In an effort to starve the cancer even in the inter-fasting periods, I tried limiting my carbohydrate as much as possible after the previous chemo/fasting session.  This wasn’t too hard, but the effect was.  I didn’t feel good.  I didn’t feel myself.  I need carbohydrates.  But I will avoid simple sugar, which lead to an immediate and strong spike in the levels of insulin and insulin-like growth factors.  Is there a way to blunt this spike?  With family birthday season – all within a month and a half – in full swing, this is a difficult thing to do.

Fat and protein are easy.  There are clear advantages and few drawbacks if you do it right.  I don’t have to change my eating habits much to do things right.  Carbohydrates are difficult.  I’m still very confused about their effects.  Not being a nutritionist doesn’t help.  Unfortunately, my hospital doesn’t have any nutritionists that specialize on the importance of diet for cancer.  This is almost criminal, but nothing I can change.  The only thing I can change is my understanding.  I need to read more.

Gaining weight is very difficult.  From looking at the world and the women’s magazines near the checkout at the grocery store, this can’t be true, but for me it is.  I still haven’t stabilized my weight between chemo sessions, which means I’m not regaining all I’ve lost during the three-plus days of fasting.  I’m still above my weight back in Utah, but not my much, and it’s worrying me.  I don’t want to have to stop fasting.  I’m convinced that fasting is good for me.  But how do I gain enough weight to stay stable over time?

What do people do to gain weight?  There are no magazine covers that address this question.  Eating crap and not moving much probably has a lot do with it.  I’m not much into either.  What do I do?  A bit of crap probably doesn’t hurt, and maybe I can move a little less.  It was probably not a good idea to go on a 20 km bike ride on Monday in search of gloves lost the previous day on a family outing by the river – not just on an empty stomach, but on a stomach that had been empty for 24 hours already.  Maybe I should take the bus to work or the hospital from time to time.  Maybe I should think less.  This uses a lot of energy.

I am trying to find a balance more than I ever have in my life.  To some extent, my life hangs in this balance.  There is obviously no guarantee that anything I do will make the slightest difference in the end, but the possibility is there, and I would be foolish not to try my hardest.  Brace yourselves.  There will be more posts on nutrition in the future.

Friday, July 3, 2020

Fake fasting

Over the past few days, I’ve mostly stuck to a low-carbohydrate diet.  I've had protein bread and peanut butter for breakfast, lots of nuts during the day and a vaguely keto dinner at night.  I've gone without chocolate, sweets or ice cream, and I’ve dropped the sugar that used to sweeten my espresso after lunch.  It’s been a strange experience.

After reading about fasting and vitamin C (and also watching the Arte documentary that my friend had in mind when he recommended fasting late last year), the thing that remained was finding out about the fasting mimicking diet that was shown to act synergistically with vitamin C.  It’s not that fasting is an unbearable burden, but if the same end can be achieved with less drastic means, I’d probably go for it.

I had great hopes in the read, but A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan is a dubious paper, to say the very least.  There are some fasting yeast, old mice that might live longer and navigate a maze slightly better than their well-fed companions, and a small number of humans that might have been fasting.  Their blood sugar and insulin levels indicate so.  The consequences are unclear.  There is no data.

The paper would be only half as pointless if it managed to explain the diet that mimics fasting (and made it into the title of the paper).  It doesn’t.  It’s not just short of detail, it’s free of any useful information.  Empty waffle, such as plant-based, calorie-restricted, low sugar, low protein, and high-fat, is presented as if it were informaion.  What does any of this mean?  Where are the numbers?  Where are the recipes or at least meal plans?  What did the volunteers who were not quite fasting do?

There are some numbers.  During fasting cycles, the volunteers restricted their caloric intake by between 46% and 66%.  Their diet was around 10% proteins, 50% fat and 40% carbohydrates.  That seems like an awful lot of carbohydrates.  And how do you get 50% from plants?  An avocado is 60% fat, but how many can you really eat over a three day period?  What did the volunteers eat?

The paper mentions “proprietary vegetable-based soups, energy bars, energy drinks, chip snacks, chamomile flower tea, and a vegetable supplement formula tablet”.  What is a chip snack?  Where do the vegetable supplement formula tablets come from?  Chamomile flower tea?  Are these guys just taking the piss?  It seems they are.  They refer to Table S4 as if it meant something, while all it contains are the same meaningless numbers that were already mentioned in the text.


Do you need a table for this?

How you get something with such shitty methods published is beyond me.  Who reviewed this paper?  It’s effectively impossible to replicate the experiments.  It’s as if I reported a crystal structure and wrote that the protein was crystallized in chemicals.  The authors dare to write that “the components and levels of micro- and macro-nutrients in the human FMD were selected based on their ability to reduce IGF-1”, but are silent on what these levels or indeed the nutrients are.  This is not science, it’s bogus.  And what are “proprietary vegetable-based soups”?  Where do they come from?  Does Fasting mimicking diet® have its own webstore?  Is this a scam?

It’s hard to tell.  Valter Longo, the senior author of this paper and many others on the beneficial effects of fasting, including the most recent connection to vitamin C, has written a book about what he calls the Longevity diet and put together a website to promote it.  You can even find some recipes there.  They don’t look particularly special, though.  How is eating these meals like fasting?  What has been removed from a normal diet besides a few calories?

This fiasco with FMD made me question what I’m doing.  I will for sure stick to my rigorous fasting regime where I understand the biochemical reasons for its beneficial effects.  On Monday, I’m starting another 80 hours.  But I have given up on the low-carbohydrate diet.  It made me feel sluggish and weak, almost as if I were still fasting.  If you can mimic fasting on 40% of carbohydrates, I shouldn’t deprive myself of them when I’m refeeding.  Apart from the sugar, I’m now back to normal with my diet, and I feel much better already.

Monday, June 29, 2020

Vitamin C and fasting

Have you read enough about vitamin C yet?  I hope not, because here’s another post.  This one will help me understand a recently published paper that shows a Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers.  To repeat myself:  I do have a KRAS-mutated cancer.  This research is potentially very relevant to me.  What I don’t have is a fasting-mimicking diet.  I’ll get to that at the very end.  But first, the paper.

As the paper is about five years more recent than the one I discussed yesterday, it takes those results for granted.  KRAS-mutated cancers don’t like high doses of vitamin C, which multiplies the oxidative stress that cancer cells have to deal with as a result of their fast proliferation.  Going beyond the earlier research, the paper envisions what might potentiate the action of vitamin C.  Fasting seems a good candidate as it also leads to increased oxidative stress in cancer cells.

The paper studies the same cell lines as the one I discussed yesterday, cell lines that carry my KRAS mutation, and shows that vitamin C kills those cells.  More cells die if they are grown in conditions that mimic starvation.  Vitamin C and fasting have a comparable individual effect on cancer cells.  The effect depends on oxidative damage and is stronger when both treatments are combined.  Add traditional chemotherapy to the equation and you get a triple whammy that cancer cells have a hard time surviving.

These are exciting results that I need to discuss with my oncologist, but words of warning are in order.  It’s a long way from a laboratory bench to a hospital bedside.  The mice that were used in this study received four grams of vitamin C per kilogram body weight twice a day.  At 62 kg, I would need to handle nearly half a kilogram of vitamin C per day, every day.  This sounds impossible but might simply be a reflection of the differences between men and mice.  Mice easily lose a quarter of their weight when they’re starved for a few days.  I lose a couple of kilograms, something like three to four per cent.  I need to find out the doses that were used in the few clinical trials that have taken place.

There’s a couple more rather obscure observations in the paper with no bearing on a possible therapeutic approach.  I’ll list them here mostly to have a reference later.

  • Cancer cells try to keep iron levels down.  Otherwise oxidative stress risks running out of control.  Vitamin C and fasting both help keep a lid on the levels of ferritin, a protein that sequesters iron.  These double negatives are common in biochemistry.  What it means is that both vitamin C and fasting (indirectly) cause iron levels to increase and, collaterally, oxidative stress.  Incidentally, low ferritin levels are correlated with increased survival of patients with KRAS mutated tumors according to the Cancer Genome Atlas Database.
  • There’s one example where vitamin C and fasting have opposite effects.  The enzyme heme oxygenase 1 increases ferritin levels.  Somewhat confusingly, vitamin C promotes the expression of this enzyme.  This leads to lower iron levels and less oxidative stress.  To exploit this, tumors often respond to chemotherapy by upregulating heme oxygenase 1 levels.  Fasting, in contrast, drives the levels of heme oxygenase 1 down.  The cells suffer more damage from oxidative stress.  Fewer of them survive.

From these data you could expect fasting to have a stronger effect on cancer cells than vitamin C, but that’s not necessarily the case according to the paper.  You might not think so after reading all this, but biochemistry is relatively straightforward.  Biology, in contrast, is much more complicated.  In living organisms, one plus one is never two.

What is it about the fasting-mimicking diet (FMD for short) that was used in the paper?  It is a way of eating that’s supposed to be easier on the body than total fasting but has much of the same beneficial effects.  FMD can slow tumor growth and make cancer cells respond better to chemotherapy.  This is exactly what is claimed for periodic fasting.  I have a number of papers on my hard drive that discuss the details of FMD.  There will be another vaguely scientific post before too long.  I have to admit it, I rather enjoy being a biochemist at the moment.

Sunday, June 28, 2020

Vitamin C and cancer

I have now read a key publication on vitamin C and my type of cancer.  On Wednesday, when I next speak to my oncologist, I will need to demand a modification to my therapy.  I have the feeling that I’m being denied better chances to survive.  The paper claims that Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.  It was published in Science, one of the beacons of scientific publishing, in 2015 with an associated commentary in the same issue.  The reason this paper isn’t just exciting but relevant is that I have a mutation in KRAS.  The two cell lines used in the paper carry the same mutation as my cancer, KRASG13D.

Let’s get started with the commentary, which should bring a bit more perspective than either research article.  It explains the complicated history of vitamin C and cancer.  It was Linus Pauling of all people who first showed cancer patients’ increased survival when they were injected high doses of vitamin C.  It's ironic that he is now primarily – and less flatteringly – associated with orally administered vitamin C.  It's even more ironic that clinical trials following up on Pauling’s research came back negative – because they also gave vitamin C orally.  It took a long time for science to recover from this mix-up and the resulting confusion.

Vitamin C is taken up by cells through dedicated vitamin C transporters.  This is of no therapeutic interest.  The oxidized form of vitamin C, which is called dehydroascorbate and always exists in equilibrium with regular vitamin C, gets into cells with the help of a glucose transporter.  This is relevant for some cancer cells whose glucose transporters are particularly active.  Inside cells, the reduction of dehydroascorbate back to vitamin C causes a spike in reactive oxygen species that block glucose metabolism (by direct inactivation of a key enzyme called glyceraldehyde 3-phosphate dehydrogenase, the GAPDH in the paper's title).  When the resulting shortage of energy inside the cell reaches crisis point, the cells die.

If the last sentence of the previous paragraph sounds vaguely familiar it’s because I’ve already written about this in a different context.  A drastically reduced food intake does of course also lead to cellular energy crises and, such is the hope behind my periodic fasting strategy, to cell death.  The point that these two approaches are synergistic is made in another paper.  Before I talk about this, I need to get into and clarify some complications.

The glucose receptor behind the uptake of vitamin C is upregulated in KRAS-mutated cancer cells.  This is why they take up more dehydroascorbate than unoxidized vitamin C, but this alone doesn’t explain the cytotoxic effect.  KRAS-mutated cancer cells reprogram their metabolism to proliferate faster.  In the process, they generate a lot of reactive oxygen species.  The antioxidant defenses that are essential for the cells to survive under high oxidative stress are inhibited by vitamin C, which contributes to the killing of the cancer cells.  It is, to make this clear, their high proliferation rate, this key feature of cancer cells that every therapy seeks to reduce, that makes them a target of vitamin C.  This is not only true for solid tumors but also, and especially, for metastatic tumor cells.  They survive the oxidizing environment of the blood by increasing their antioxidant defenses.  Vitamin C is thus expected to kill circulating metastatic tumor cells as well.  This works, as the paper shows, even when the cells are grown in normal glucose conditions.

It’s not as easy as this, of course.  One can’t take basic research and transfer it into the clinic.  What works in cell culture might not work in patients.  From the results it is unclear whether vitamin C has a therapeutic use for the treatment of KRAS-mutated cancers.  At the time the paper was published in 2015, there was an early clinical trial that looked at the effect of vitamin C in conjunction with platinum-based chemotherapy.  I haven’t had the time yet to dig into this and see what the outcome was and whether there have been related trials since then.

This post is full of information that’s not of the most easily digestible kind.  It’s probably best I stop at this point, but not before summarizing in the clearest language I can manage:

Cancer cells with KRAS mutations are killed by high levels of vitamin C.  The biochemistry works like this:

  • Cancer cells primarily consume the oxidized form of vitamin C.
  • The reduction of oxidized vitamin C inside the cell causes oxidative stress.
  • Oxidative stress leads to the inactivation of an enzyme that helps turn glucose into energy.
  • Lack of this enzyme leads to a scarcity of available energy to which cells respond by conking out.

The question of a possible synergy between vitamin C and fasting will be the topic of the next post.

Friday, June 26, 2020

Vitamin C

I’m going down a rabbit hole again.  The one paper on the synergistic effects of fasting and vitamin C that my friend sent the other day led me to download a good dozen related publications.  Reading them will take some time.  Synthesizing and condensing all the information will take even longer.  But there’s no reason not to forge ahead with what I've got already.  Let’s get started with vitamin C.  I don’t have to read papers for that.  Wikipedia and the internet in general tell me all I need to know.

Vitamin C is a fairly simple organic compound and an essential nutrient.  It is involved in tissue repair and important for the function of the immune system.  It also functions as an antioxidant, which means it can mitigate oxidative damage to proteins and DNA.  Humans – in contrast to most animals – cannot make it themselves.  It needs to be consumed with food or as dietary supplements.  For most people, a reasonably healthy diet is all it takes to get enough vitamin C.  The story could end here but it doesn’t.

Many decades ago, the great chemist Linus Pauling hypothesized that elevated levels of vitamin C give all sorts of benefits, from beating the common cold to longer, healthier lives.  His megavitamin theory keeps floating around in various incarnations that are promoted by Pauling’s acolytes to this day.  Health food stores sell big tubs of vitamin C, but the idea behind it has been debunked.

The Office of Dietary Supplements, which sounds like a Monty Python sketch but is in reality an information dispensary of the National Institutes of Health, writes that consuming increased amounts of vitamin C is of limited value.  Its tissue and plasma levels are tightly controlled.  The more vitamin C is consumed, the smaller the share that’s absorbed.  Popping more pills won’t do much.  Most of the stuff leaves the body straight away through strained kidneys.  The narrow range of allowed concentrations probably determines the antioxidant properties of vitamin C.

How can high doses of vitamin C then help the body fight cancer?  The key here is that we’re talking about intravenous administration and not oral consumption.  Put vitamin C straight into the blood, and you can reach concentrations around 100 times higher than by ingestion.  Such high levels may change the properties of vitamin C from antioxidant to pro-oxidant.  The potential generation of hydrogen peroxide with selective toxicity toward cancer cells is quite exciting.  In the next post, I’m going to dig through some of the studies of the relationship between vitamin C and my cancer.