9 ms·

My father was on chemotherapy with fludarabine, a dna base analog. The way it functions is that it is used in DNA replication, but then doesn’t work, and the d

by raylad 1y ago

My father was on chemotherapy with fludarabine, a dna base analog. The way it functions is that it is used in DNA replication, but then doesn’t work, and the daughter cells die. Typically, patients who get this drug experience a lot of adverse effects, including a highly suppressed immune system and risk of serious infections. I researched whether there was a circadian rhythm in replication of either the cancer cells or the immune cells: lymphocyte and other progenitors, and found papers indicating that the cancer cells replicated continuously, but the progenitor cells replicated primarily during the day. Based on this, we arranged for him to get the chemotherapy infusion in the evening, which took some doing, and the result was that his immune system was not suppressed in the subsequent rounds of chemo given using that schedule. His doctor was very impressed, but said that since there was no clinical study, and it was inconvenient to do this, they would not be changing their protocol for other patients. This was around 1995.

sixo 1y ago
Amazing. And shameful (for them.)
- ch4s3 1y ago
  It’s not shameful, it’s how evidence based medicine works. One case is interesting but not a basis for changing a protocol by itself. Tons of things could have influenced the outcome and you need a proper study to know that.
  - wyldfire 1y ago
    Though it could certainly inspire such a study.
    - ch4s3 1y ago
      Sure, but someone needs to fund, organize, and conduct the study. If you're not at a research hospital it's not as easy for a one off case to generate a study.
      - vlovich123 1y ago
        This is a fairly innocuous change the doctor should be organizing on their own to publish a pilot study. In terms of funding very little would be required since you’re just making a small adjustment to when an existing drug regimen is happening which you already isn’t a controlled factor requiring FDA oversight or anything.
        _qua 1y ago
        Even simple studies are expensive and difficult. You need IRB approval, data collection and organization, staff to do those things. It seems simple from the outside but making it happen takes time, effort, and money which then means also applying for grants which is a process in and of itself.
        renewiltord 1y ago
        Indeed, as any ethicist worth his salt would argue: we don’t want anyone saving lives without proper approval.
        vkou 1y ago
        Any ethicist worth your salt would presumably have no problem approving experiments that will also cost lives. There are an endless number of parameters in medicine that can be fiddled with. If an N=1 sample were enough to convince you, all sorts of garbage would meet that pattern.
        refurb 1y ago
        What a intellectually lazy response. No, it would be more accurate to say "any ethicist worth his salt would argue: don't make changes that could be harmful based on a hunch"
        southernplaces7 1y ago
        I think it was a bit tongue in cheek, not so much lazy. Also, considering the kinds of gatekeeping and forced "concerns" I've seen some ethicists push forth just for the sake of showcasing their fixations instead of really looking at costs and benefits, I don't think it's far off the mark on reality to argue that medical ethics is worth considerable scrutiny too, and shouldn't hid behind a mantle of being above criticism.
  - AbrahamParangi 1y ago
    The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child. There are many things that are simply uncertain and “untrue until proven otherwise” isn’t an exclusively optimal policy.
    - raverbashing 1y ago
      It's ok, the strongest defenders of EBM are never going to discover anything worthwhile as they get caught in a loop of "no evidence enough to test" and "no evidence for this because nobody tests it"
      - vrc 1y ago
        Counterpoints: the detractors of this purported loop would likely neither fund the vast amounts of research they’d demand be done nor believe the results if they conflicted with their anecdata. I have yet to see a good faith argument against evidence based method that provides an effective and realistic alternative. Because that would take evidence.
      - ch4s3 1y ago
        The opposite approach exposes people to a lot of unnecessary and dangerous medical treatment. The evidence based approach has uncovered that stenting doesn't work[1], yet a lot of do something proponents are still installing them at great risk to patients and at great cost to medical systems. [1] https://lowninstitute.org/stents-dont-work-a-look-back-at-the-research/ https://lowninstitute.org/stents-dont-work-a-look-back-at-th...
    - h2782 1y ago
      > The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child. What? This makes no sense. How do you explain anti-vaxxer parents with this perspective? Parents may feel they know best, but feeling and fact have nothing to do with each other.
  - echelon 1y ago
    > It’s not shameful, it’s how evidence based medicine works. Yeah, but I'll bet nothing happened as an outcome of this. No study, no communication to anyone else. That information probably just withered on the vine. I did a molecular bio undergrad and had classes with a bunch of pre-med students. They had zero interest in the science, just getting A's. They did care about appearance and money, driving cool cars, and dating hot partners. I know my experience is purely anecdotal and not indicative of all doctors, but I came away from my undergrad experience highly unimpressed with our medical feedstock. The only students in upper level electives that cared were the research-track students. I talk to my doctors regularly about medicinal chemistry and biochem -- they don't know anything. It's embrassing how little they retain or care.
    - calf 1y ago
      "Evidence-based" is a really problematic term when it is used to protect bureaucracies and medical managerialism, rather than actually interact with scientific processes in an ethical way. Their anecdote is actually a good example of why evidence-based logic is not the end-all.
      - uselesswords 1y ago
        [flagged]
        echelon 1y ago
        Barry James Marshall
        uselesswords 1y ago
        [flagged]
        uselesswords 1y ago
        Since no one wants to explain and you I just got downvoted, Barry James Marshall is ironically an example of EBM and is HIMSELF an active proponent of EBM. He had a biological hypothesis that the scientific community disagreed with and tested it on himself for a case study to get data. That case study was successful and then became a clinical trial. That trial was replicated and shown to work. He then won a Nobel prize for that work and the risk he took. This is an evidence-based process. EBM doesn’t mean you disregard a N=1, it means you expand N=1 into N=10, then N=100,… before you apply something to the general population. This is loosely how phase-1,2,3,4 trials work in the US. Dismissing EBM because of Marshall is like dismissing all of math because someone disproved a popular conjecture like the local-to-global conjecture. Sure the community sentiment had it wrong, but the systematic logical approach of Math got it right. In Marshall’s case the community sentiment had it wrong, but the EBM approach eventually got it right. Half this thread doesn’t even know what they are arguing against.
  - teekert 1y ago
    It is not shameful indeed. One never knows what the father had experienced if he had been given the therapy during the day. The oncologist could have written a paper (there are many single case papers), or started a trial by himself (requires a lot of organizing) if he was very intrigued. But of course one can’t do that for every above average case. I have to say, in this particular case there is a very plausible mechanism and the trial would not be that hard. So it is a real shame that nothing was done with this.
    - raylad 1y ago
      Previous rounds of chemo were done on the normal morning infusion schedule and he ended up with a completely depleted immune system and was put in strict quarantine. He also got multiple infections that were life threatening. This is the reason I started looking into the alternate dosing schedule.
  - jcims 1y ago
    Well the concept is now being studied quite closely. Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced. https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/ https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/ I'm comfortable calling that shameful. Not on any one in particular, it's a systemic problem that could be reduced with sufficient tenacity and courage to take risks.
    - ch4s3 1y ago
      There's limited time and a finite supply of doctors and researchers. They can't study everything that's promising all at once, and good ideas fall through the cracks all of the time.
      - JamesSwift 1y ago
        I think this clears a bar of things that are useful and simple to study. Theres basically no effort involved. If it ends up beneficial we just update job postings from 'daytime infusion tech' to 'nighttime infusion tech'. Instant improvement in outcomes. I doubt you even need to clear this in any way to get the study greenlit.
        jcims 1y ago
        Agreed. Scheduling is patient discretion anyway. It's the lowest bar possible as far as I can tell.
    - refurb 1y ago
      > Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced. You can only say that with hindsight because of the data over the past 30 years. What if the data showed the opposite? Then the doctor would have given his patients a worse outcome all on a "hunch".
- vkou 1y ago
  > And shameful (for them.) 1. A single positive outcome with N=1 should generally not be the basis for making a medical recommendation. 2. It takes a mountain of research work to go from that to a study that you can draw meaningful conclusions from. 3. The hospital is not in the business of doing research, it's in the business of treating patients.
  - tilne 1y ago
    Regarding 3: Shouldn’t the medical system be optimizing for patient outcomes rather than the business their in? Regarding the first two: I think the anecdote being from 1995 suggests there would have been time to put together said mountain of research. I’m not agreeing that this is shameful for the original doctor, but I do think it’s shameful if avenues for potential research are not taken because it’s inconvenient for the hospitals.
    - vkou 1y ago
      Yes, it should. But cost is also important to patients. Or it would be in any universe that made sense.
    - Spooky23 1y ago
      It is at cancer centers. Community oncologists don’t have the resources to do it. Example: https://www.medicalnewstoday.com/articles/cancer-time-of-day-may-matter-for-diagnosis-treatment#How-circadian-rhythm-affects-cancer-treatment https://www.medicalnewstoday.com/articles/cancer-time-of-day...
      - raylad 1y ago
        This was Sloan-Kettering. They gave morning infusions because it was convenient. To get my father the evening infusion we had to hire private duty nurses to come to his apartment.
  - vlovich123 1y ago
    I agree n=1 generally isn’t enough, but something like this is easily something you ask for volunteers for as an experiment. There’s 0 risk, you’re taking the same drug. The only reason a given time is selected anyway is for administrative ease not because there’s medical requirements.
- bravesoul2 1y ago
  What's the p value? 0.5?
irrational 1y ago
Is it the time of day or how long the patient has been awake that matters? It seems like someone could change their sleep cycle to match the doctors schedule if the latter.
HexPhantom 1y ago
It's frustrating (but not surprising) that even with a clear positive outcome, the system couldn't adapt without a clinical trial to back it up
- taneliv 1y ago
  Isn't it also quite understandable? Otherwise we risk the new way working well for half the patients and killing the other half, to exaggerate.
bloqs 1y ago
As a younger person what are the best habits to get into to maintain optimal long term immune health?
- ReptileMan 1y ago
  Normal weight and enough sleep.
- throwaway290 1y ago
  Don't compromise it chronically. Protected sex etc.
- goda90 1y ago
  Sleep, exercise, a balanced diet of mostly whole fruits and vegetables, and a moderate amount of whole grains, legumes and fresh meat/fish/eggs if you're not choosing a vegan lifestyle. Avoid ultra processed foods, cured meats, alcohol and other recreational drugs. Make sure you get enough vitamin D, which can be hard with certain diets if you're not supplementing, or getting the right amount of sunlight(latitude and time of year matters). Try to stay low stress, spend time out in nature, maintain good relationships, etc. Edit: caveat to spending time out in nature: be vigilant of ticks. A tick-bourne disease can mess up your immune system pretty well
  - FollowingTheDao 1y ago
    Maybe your schema will work for someone who’s on the very top point of the bell curve of human population but human genetic and environmental variability will over rule your advice for the majority of people.
    - pinkmuffinere 1y ago
      The states known for “hippie”/“granola” attitudes, which largely align with the advice given here, tend to live longer than the states that don’t (scroll through the list in [1] to see this). Usually I would insist on a study, but the effect is so striking, and the mechanism by which it would work is so obvious, that I think this simple list is enough. And I’m sure there are studies too, I’m just too lazy to find and link one. [1] https://en.wikipedia.org/wiki/List_of_U.S._states_and_territories_by_life_expectancy?wprov=sfti1 https://en.wikipedia.org/wiki/List_of_U.S._states_and_territ...
jcims 1y ago
You were obviously on to something and it's frustrating yet completely expected to see all replies with pat dismissals that anything like this gets when there is some real potential innovation in healthcare. Google 'chronotherapy' with some chemo/cancer/immunotherapy related terms and you'll find a ton of research being done. Given that most of it seems to have evolved in the last 8 years my guess is that the concept was 'vetted' by a nobel prize in 2017 for molecular circadian clock, so people feel safe putting their name on studies in this area.
- refulgentis 1y ago
  ? The other replies don't dismiss it...
Gravityloss 1y ago
I've heard similar things about fasting.

by raylad 1y ago

sixo 1y ago

Amazing. And shameful (for them.)

ch4s3 1y ago
It’s not shameful, it’s how evidence based medicine works. One case is interesting but not a basis for changing a protocol by itself. Tons of things could have influenced the outcome and you need a proper study to know that.
- wyldfire 1y ago
  Though it could certainly inspire such a study.
  - ch4s3 1y ago
    Sure, but someone needs to fund, organize, and conduct the study. If you're not at a research hospital it's not as easy for a one off case to generate a study.
    - vlovich123 1y ago
      This is a fairly innocuous change the doctor should be organizing on their own to publish a pilot study. In terms of funding very little would be required since you’re just making a small adjustment to when an existing drug regimen is happening which you already isn’t a controlled factor requiring FDA oversight or anything.
      - _qua 1y ago
        Even simple studies are expensive and difficult. You need IRB approval, data collection and organization, staff to do those things. It seems simple from the outside but making it happen takes time, effort, and money which then means also applying for grants which is a process in and of itself.
        renewiltord 1y ago
        Indeed, as any ethicist worth his salt would argue: we don’t want anyone saving lives without proper approval.
        vkou 1y ago
        Any ethicist worth your salt would presumably have no problem approving experiments that will also cost lives. There are an endless number of parameters in medicine that can be fiddled with. If an N=1 sample were enough to convince you, all sorts of garbage would meet that pattern.
        refurb 1y ago
        What a intellectually lazy response. No, it would be more accurate to say "any ethicist worth his salt would argue: don't make changes that could be harmful based on a hunch"
        southernplaces7 1y ago
        I think it was a bit tongue in cheek, not so much lazy. Also, considering the kinds of gatekeeping and forced "concerns" I've seen some ethicists push forth just for the sake of showcasing their fixations instead of really looking at costs and benefits, I don't think it's far off the mark on reality to argue that medical ethics is worth considerable scrutiny too, and shouldn't hid behind a mantle of being above criticism.
- AbrahamParangi 1y ago
  The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child. There are many things that are simply uncertain and “untrue until proven otherwise” isn’t an exclusively optimal policy.
  - raverbashing 1y ago
    It's ok, the strongest defenders of EBM are never going to discover anything worthwhile as they get caught in a loop of "no evidence enough to test" and "no evidence for this because nobody tests it"
    - vrc 1y ago
      Counterpoints: the detractors of this purported loop would likely neither fund the vast amounts of research they’d demand be done nor believe the results if they conflicted with their anecdata. I have yet to see a good faith argument against evidence based method that provides an effective and realistic alternative. Because that would take evidence.
    - ch4s3 1y ago
      The opposite approach exposes people to a lot of unnecessary and dangerous medical treatment. The evidence based approach has uncovered that stenting doesn't work[1], yet a lot of do something proponents are still installing them at great risk to patients and at great cost to medical systems. [1] https://lowninstitute.org/stents-dont-work-a-look-back-at-the-research/ https://lowninstitute.org/stents-dont-work-a-look-back-at-th...
  - h2782 1y ago
    > The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child. What? This makes no sense. How do you explain anti-vaxxer parents with this perspective? Parents may feel they know best, but feeling and fact have nothing to do with each other.
- echelon 1y ago
  > It’s not shameful, it’s how evidence based medicine works. Yeah, but I'll bet nothing happened as an outcome of this. No study, no communication to anyone else. That information probably just withered on the vine. I did a molecular bio undergrad and had classes with a bunch of pre-med students. They had zero interest in the science, just getting A's. They did care about appearance and money, driving cool cars, and dating hot partners. I know my experience is purely anecdotal and not indicative of all doctors, but I came away from my undergrad experience highly unimpressed with our medical feedstock. The only students in upper level electives that cared were the research-track students. I talk to my doctors regularly about medicinal chemistry and biochem -- they don't know anything. It's embrassing how little they retain or care.
  - calf 1y ago
    "Evidence-based" is a really problematic term when it is used to protect bureaucracies and medical managerialism, rather than actually interact with scientific processes in an ethical way. Their anecdote is actually a good example of why evidence-based logic is not the end-all.
    - uselesswords 1y ago
      [flagged]
      - echelon 1y ago
        Barry James Marshall
        uselesswords 1y ago
        [flagged]
        uselesswords 1y ago
        Since no one wants to explain and you I just got downvoted, Barry James Marshall is ironically an example of EBM and is HIMSELF an active proponent of EBM. He had a biological hypothesis that the scientific community disagreed with and tested it on himself for a case study to get data. That case study was successful and then became a clinical trial. That trial was replicated and shown to work. He then won a Nobel prize for that work and the risk he took. This is an evidence-based process. EBM doesn’t mean you disregard a N=1, it means you expand N=1 into N=10, then N=100,… before you apply something to the general population. This is loosely how phase-1,2,3,4 trials work in the US. Dismissing EBM because of Marshall is like dismissing all of math because someone disproved a popular conjecture like the local-to-global conjecture. Sure the community sentiment had it wrong, but the systematic logical approach of Math got it right. In Marshall’s case the community sentiment had it wrong, but the EBM approach eventually got it right. Half this thread doesn’t even know what they are arguing against.
- teekert 1y ago
  It is not shameful indeed. One never knows what the father had experienced if he had been given the therapy during the day. The oncologist could have written a paper (there are many single case papers), or started a trial by himself (requires a lot of organizing) if he was very intrigued. But of course one can’t do that for every above average case. I have to say, in this particular case there is a very plausible mechanism and the trial would not be that hard. So it is a real shame that nothing was done with this.
  - raylad 1y ago
    Previous rounds of chemo were done on the normal morning infusion schedule and he ended up with a completely depleted immune system and was put in strict quarantine. He also got multiple infections that were life threatening. This is the reason I started looking into the alternate dosing schedule.
- jcims 1y ago
  Well the concept is now being studied quite closely. Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced. https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/ https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/ I'm comfortable calling that shameful. Not on any one in particular, it's a systemic problem that could be reduced with sufficient tenacity and courage to take risks.
  - ch4s3 1y ago
    There's limited time and a finite supply of doctors and researchers. They can't study everything that's promising all at once, and good ideas fall through the cracks all of the time.
    - JamesSwift 1y ago
      I think this clears a bar of things that are useful and simple to study. Theres basically no effort involved. If it ends up beneficial we just update job postings from 'daytime infusion tech' to 'nighttime infusion tech'. Instant improvement in outcomes. I doubt you even need to clear this in any way to get the study greenlit.
      - jcims 1y ago
        Agreed. Scheduling is patient discretion anyway. It's the lowest bar possible as far as I can tell.
  - refurb 1y ago
    > Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced. You can only say that with hindsight because of the data over the past 30 years. What if the data showed the opposite? Then the doctor would have given his patients a worse outcome all on a "hunch".
vkou 1y ago
> And shameful (for them.) 1. A single positive outcome with N=1 should generally not be the basis for making a medical recommendation. 2. It takes a mountain of research work to go from that to a study that you can draw meaningful conclusions from. 3. The hospital is not in the business of doing research, it's in the business of treating patients.
- tilne 1y ago
  Regarding 3: Shouldn’t the medical system be optimizing for patient outcomes rather than the business their in? Regarding the first two: I think the anecdote being from 1995 suggests there would have been time to put together said mountain of research. I’m not agreeing that this is shameful for the original doctor, but I do think it’s shameful if avenues for potential research are not taken because it’s inconvenient for the hospitals.
  - vkou 1y ago
    Yes, it should. But cost is also important to patients. Or it would be in any universe that made sense.
  - Spooky23 1y ago
    It is at cancer centers. Community oncologists don’t have the resources to do it. Example: https://www.medicalnewstoday.com/articles/cancer-time-of-day-may-matter-for-diagnosis-treatment#How-circadian-rhythm-affects-cancer-treatment https://www.medicalnewstoday.com/articles/cancer-time-of-day...
    - raylad 1y ago
      This was Sloan-Kettering. They gave morning infusions because it was convenient. To get my father the evening infusion we had to hire private duty nurses to come to his apartment.
- vlovich123 1y ago
  I agree n=1 generally isn’t enough, but something like this is easily something you ask for volunteers for as an experiment. There’s 0 risk, you’re taking the same drug. The only reason a given time is selected anyway is for administrative ease not because there’s medical requirements.
bravesoul2 1y ago
What's the p value? 0.5?

irrational 1y ago

Is it the time of day or how long the patient has been awake that matters? It seems like someone could change their sleep cycle to match the doctors schedule if the latter.

HexPhantom 1y ago

It's frustrating (but not surprising) that even with a clear positive outcome, the system couldn't adapt without a clinical trial to back it up

taneliv 1y ago
Isn't it also quite understandable? Otherwise we risk the new way working well for half the patients and killing the other half, to exaggerate.

bloqs 1y ago

As a younger person what are the best habits to get into to maintain optimal long term immune health?

ReptileMan 1y ago
Normal weight and enough sleep.
throwaway290 1y ago
Don't compromise it chronically. Protected sex etc.
goda90 1y ago
Sleep, exercise, a balanced diet of mostly whole fruits and vegetables, and a moderate amount of whole grains, legumes and fresh meat/fish/eggs if you're not choosing a vegan lifestyle. Avoid ultra processed foods, cured meats, alcohol and other recreational drugs. Make sure you get enough vitamin D, which can be hard with certain diets if you're not supplementing, or getting the right amount of sunlight(latitude and time of year matters). Try to stay low stress, spend time out in nature, maintain good relationships, etc. Edit: caveat to spending time out in nature: be vigilant of ticks. A tick-bourne disease can mess up your immune system pretty well
- FollowingTheDao 1y ago
  Maybe your schema will work for someone who’s on the very top point of the bell curve of human population but human genetic and environmental variability will over rule your advice for the majority of people.
  - pinkmuffinere 1y ago
    The states known for “hippie”/“granola” attitudes, which largely align with the advice given here, tend to live longer than the states that don’t (scroll through the list in [1] to see this). Usually I would insist on a study, but the effect is so striking, and the mechanism by which it would work is so obvious, that I think this simple list is enough. And I’m sure there are studies too, I’m just too lazy to find and link one. [1] https://en.wikipedia.org/wiki/List_of_U.S._states_and_territories_by_life_expectancy?wprov=sfti1 https://en.wikipedia.org/wiki/List_of_U.S._states_and_territ...

jcims 1y ago

You were obviously on to something and it's frustrating yet completely expected to see all replies with pat dismissals that anything like this gets when there is some real potential innovation in healthcare. Google 'chronotherapy' with some chemo/cancer/immunotherapy related terms and you'll find a ton of research being done. Given that most of it seems to have evolved in the last 8 years my guess is that the concept was 'vetted' by a nobel prize in 2017 for molecular circadian clock, so people feel safe putting their name on studies in this area.

refulgentis 1y ago
? The other replies don't dismiss it...

Gravityloss 1y ago

I've heard similar things about fasting.