Administering immunotherapy in the morning seems to matter. Why?
owlposting.com
owlposting.com
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.
When I did my bio undergrad I was keenly aware our bodies are just scaled up molecular machines. I was hoping for a future where we'd grow MHC-neutral clonal bodies for organ harvesting.
Nope. We're in the stone age.
Clone humans. Cut off their brain stem during development. Turn off cephalization signals for good measure. Scale it up to industrial scale.
Research problems solved.
We'd have every study at our fingertips. We'd have organs and tissue and blood for everyone.
We could possibly even do whole head transplants and cure all non-blood, non-brain cancers.
But we're playing in the sand.
If you toss out the old rule book and provide unlimited funding, it can be made to work.
Our bodies are bigger machines made of lots of little machines.
Our minds or conscious egos or "souls" are the neurotransmitter and activation activity of the connectome and all of its cells and synaptic weights and metabolic activity. They're our lived experiences for as long as our brains can function. Minds experience and produce wonderful things.
If you divorce the body from the mind, there is no "person". Just a very complicated machine. A very valuable machine full of parts.
A human body in a vegetative state is not a person. It's a dormant machine. People may have emotional attachment to that vestige, but it is no longer capable of being a person. It is not a person.
We use brain dead humans for organ transplant all the time. If you understand the premise, then it isn't that far-fetched that we might grow vegetative humans in a lab for medical use and research.
Bodies that never have brains can never become persons. They're no different from plants.
There is decent experimental evidence to demonstrate that we are more than gene expression and the machine analogy you insist on is not a good one for understanding biological systems - see work by Michael Levin, as example.
There is a wider paradigmatic shift underway that moves from thinking about parts to processes. This refocus on relations rather than objects is very important and, for biological systems, points to a fundamentally social/collective aspect to their nature.
The machine metaphor also fails when you can no longer explain how the machine works. This is true in many areas of medicine (e.g. anasthesia) and, while we continue to believe (sometimes with enormous zeal) in the concepts that helped us in the past, we cling to them at the cost of building better understanding.
What you say isn't "wrong", but it is too limited to be a useful guide in asking new questions about things like immunotherapy treatments.
There is a difference between "reasonable guardrails" and suffocating progress until it's nearly impossible barring Herculean efforts by multibillion dollar entities. It cannot be understated how badly the current bureaucracy has destroyed medical progress.
We are seeing the same problem with nuclear overregulation result in worse outcomes and more deaths for people globally.
There is real suffering and a human cost, measurable in lives, to slowing down progress - just as there is one for reckless progress.
The medical journals are filled with studies that "should have worked" and didn't.
Heck, there are a ton of studies that "should have worked" that were harmful.
So much for "we're just scaled up molecular machines".
> the process has become more important than the problem you’re trying to solve.
We have a word for this, which roughly translates to "rule of paperwork". Bureaucracy.
Do I keep going or is the IRB approval process clearer now? There is a reason it exists.
We're talking about a factor that no one has previously had reason to consider important.
Of course, I don't know hard it truly is to undertake a study. I have to imagine for something like this you could write up a basic study protocol in fairly short order.
> How do you ensure you collected enough of a sample of a general population to make your study representative?
You don’t need to. This would be a pilot study to check whether there’s maybe a there there before you do it larger scale to measure predictive power at population level.
> Do I keep going or is the IRB approval process clearer now? There is a reason it exists.
I think you’re completely failing to engage with the argument that this particular case about time shifting delivery of a drug should not need meaningful IRB engagement other than “I’d like to change the time I deliver the drug for 2 more patients because we had one patient respond positively and this isn’t believed to be a factor” “ok cool yup”.
You’ve jumped from no IRB to full IRB without considering the context of the problem being solved which is why I said when the process becomes the goal vs the problem you’re trying to solve - you’re imaging the worst and most complicated situations possible for a case that would never demand it.
> The IRB is often in place not to stop positive outcomes, but to reduce negative ones.
Research can literally be IRB exempt if it provides minimal or no risk to patients which is literally what this is. Even if you put this in the "minimal risk" category which would be extreme that's still minimal IRB oversight and approval takes ~1-3 weeks.
You're imagining IRB is something it's not even intended to be and then saying it's a reasonable bottleneck in general because of real problems it prevents and thus justified for this specific experiment (where it wouldn't be relevant).
This is top to bottom a failure to follow up - doctor's are overworked & fail to follow up on potential research results because they act more like mechanics.
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.
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"
There are many things that are simply uncertain and “untrue until proven otherwise” isn’t an exclusively optimal policy.
[1] https://lowninstitute.org/stents-dont-work-a-look-back-at-th...
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.
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.
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.
If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.
If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.
However, your "It's great that you're in medical school and very aware" is very patronizing and pointedly dismissive. Its a superficially polite acknowledgment that feels sarcastic rather than genuinely complimentary. I don't really mind, and I acknowledge the point you're trying to make. But if your goal is to curate a curious discussion and avoid snark you should model it too.
It's all too easy to fall into, and we do it too. In such cases it's good when people point it out, and I'm happy to take my own medicine.
The fix is to be more mindful of how easily this happens and edit one's comments to err on the side of unsnark. That's what I will do. If you're willing to do that as well, then HN will be better off in both cases.
(I do think it's great that you're in medical school and willing to share some of what you know on HN, but I shouldn't have singled out the "very aware" bit - that was me being passive-aggressive.)
Also medicine is an evidence-based practice because fundamentally our knowledge is woefully incomplete. Doctors are basically applied statisticians, the chemistry and biochemistry people are the researchers.
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.
This is the reason I started looking into the alternate dosing schedule.
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.
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".
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.
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.
But cost is also important to patients. Or it would be in any universe that made sense.
Example: https://www.medicalnewstoday.com/articles/cancer-time-of-day...
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.
That they did it for one patient does not mean that they can do it for everyone - especially when it's not clear if it actually helped, due to a small sample size.
Nowhere do you start from 0 and go to 100. You take baby steps scaling up to see if the results hold.
This was Sloan-Kettering.
They gave morning infusions because it was convenient for them.
To get my father the evening infusion we had to hire private duty nurses to come to his apartment.
Since they clearly could alter the schedule, offering a limited number of later slots and comparing results would seem like the prudent response.
There's a difference between a doctor entertaining a medically-irrelevant suggestion from a patient (or patient's family), vs. assuming that the subsequent improvement was related to it, and then making that decision for some other patients (or suggesting it to them). The former is being accommodating, the latter is making treatment changes without good reason.
Improvement or no change aren't the only two possible outcomes for a patient. They could also get worse. What's worse, often neither improvement nor decline are obviously related to the treatment, or treatment changes.
Maybe it's the circadian rhythm thing. Maybe it's some delayed effects of something unrelated about the patient, that just coincided with your intervention. Maybe it's just a response to a change - any change. Or maybe it's just completely random. The point is, you don't know. You might feel like you do, or maybe it really looks obvious - but from N=1 you don't actually know, not enough to potentially bet other people's health on it.
Because maybe you do go ahead, and make a schedule change to another few patients - and few days later, suddenly and for no apparent reason, one of them goes into critical condition and dies soon after. Good luck convincing the grieving family, your colleagues, the board - and your own conscience - that the schedule change could not have possibly caused this. You won't, because you don't actually know.
They could already have made it worse with prior scheduling decisions, without having any idea.
Intentionally choosing to ignore a possibly harmful effect of the current lack of scheduling rules seems to me as blatantly unethical or worse as taking reasonable steps within what is already permitted to try to address a possible negative effect.
If concerned about making the schedule change for them: Provide the option. Add appropriate warnings if you like.
But also consider that any grieving families that finds out after the fact that there might be a known benefit to changing the scheduling would be equally hard to convince that you've not acted unethically and done harm.
In a sense, yes - but there's a difference between following established protocol or understanding, vs. changing it; the difference comes from operating under extreme uncertainty. It's a version of "if it ain't broken, don't fix it" - especially if you're not able to fully commit to identifying the problem, devising a fix, and verifying it's actually doing what you expect for reasons you expected.
> They could already have made it worse with prior scheduling decisions, without having any idea.
Or they could've made it better without having any idea. Point is, they had no idea either way.
> If concerned about making the schedule change for them: Provide the option. Add appropriate warnings if you like.
Even providing an option is already biasing the patient's decisions. Especially in matters of health, people will happily ignore all the warnings you can give (especially if they're mostly philosophical points about ethics or epistemology) and grasp for anything that could help. They're not going to be making a calm and objective choice. Doctors are fully aware of this, and with that awareness, presenting an option is really making a decision for yourself, but dumping any potential fallout on a patient. It's the 21st century, we know what informed choice is, and that wouldn't be it.
> But also consider that any grieving families that finds out after the fact that there might be a known benefit to changing the scheduling would be equally hard to convince that you've not acted unethically and done harm.
For better or worse, that's a big part of what evidence-based medicine is - a shield to protect you in situations like these. It lets you say that "might" wasn't enough - that the benefit wasn't actually "known", but merely anecdotally reported; that the benefit could be real, or could be coincidence, and there could be drawbacks too, unknown or under-reported (so the family didn't stumble on anecdotes of failure like did on anecdotes of success). It lets you say that there is an actual framework for evaluating what's ethical under uncertainty, and it deemed the risk too high. Most importantly, it lets you say all that, and have the entire medical community back you on this. Whether or not your conscience agrees, at the very least the will judge you as acting ethically and in best interest of the patient.
EBM and standard protocols are far from perfect - but they have solid ethical and epistemological grounding, and achieve the goal of minimizing harm to the extent possible under extreme uncertainty the medical field operates in.
2. Does it? Speaking directly out of my butt here (not in healthcare, not an academic), but the OP spoke of pretty acute symptoms specific to a treatment plan. If the treatment program is at all common, then a very straightforward A/B split of non-intervention / intervention.
Heck, even a questionnaire of past patients cross-referenced with historical records of appointment times could go a long way to validate the hypothesis.
3. This degree of specialization is for insects. If literal MDs in the field are too atomized to even surface research proposals, then that feels like an awful waste of edge-research capability.
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
[1] https://en.wikipedia.org/wiki/List_of_U.S._states_and_territ...
Try not to take any medicines unless you absolutely need them, and stay away from hand sanitizers. If you do need to clean anything, soap is more than enough and water is usually enough.
I thought it was normal to be over 50 and not take any medicines, but all the doctors and staff were surprised by this when I got my colonoscopy recently.
That said, unfortunately there's some element of luck to it. There's compelling evidence that C-section babies have abnormal immune responses and less diverse body flora. And I imagine childhood circumstance affects things too, city vs country affecting the childhood exposure to pathogens and non-pathogens for training.
So I am rather with you. It should be normal not to take medicines.
- practice safe sex, get tested regularly (even if both you and your partners are exclusive) and get that HPV shot. Yes, even if you're male. Cancer on your bits ain't pretty.
- keep the drug consumption reasonable, especially smoking and alcohol
- the better quality the food, the better your health. Should be a no-brainer and I know about food deserts, lack of time etc
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.
I had awful ulcers in my mouth from the chemo drug and had been taking the folic acid in the morning. Through forgetfulness I ended up shifting the folic acid to the afternoon and the ulcers went away and never came back.
Most people also fast at night (sleeping) and are less physically active etc etc.
glucose level? low in the morning, and cancer likes glucose (among other effects of low glucose a cancer site would probably have lower local acidity, and the high local acidity is one of the tools used by cancer to protect and spread itself) .
That’s a powerful analog for depression and burnout in humans.
I should know better by now than to trust doctors to act based on research and not gut feeling, but I hope this doesn't mean the last year of taking it was a wash...
Always remember what you are just an another patient with your own quirks.
do you carry any of the blame on yourself since you knew there were explicit instructions but apparently waiting to shower or exercise was too much of an inconvenience for you?
> There’s a really interesting phenomenon in the immunotherapy field that has been going on for what seems to be several years now
> All of this culminated in a really incredible review paper
(review paper references papers from multiple years prior)
And no, it's absurd to imply I do carry blame here. I'm not a medical professional and that's exactly why I asked two specialists for help understanding the criticality of the instructions... that's the point. Even if they didn't know, they could have deferred to the written instructions rather than coming up with an original conclusion.
Say exactly what matters.
E.G. 'Take once a day at a similar time.' VS overly specific but not required 'take in the morning / evening / lunch / some other assumption that doesn't matter.' HOWEVER maybe "Take once a day with your first (full) meal." OR "Take once a day with your primary meal." might make more sense for medications that interact with food.
Have either you or your doctor identified the reason for the morning recommendation?
Maybe restart consideration of timing there?
Doctors are going to take your practical need to break one part of protocol, to maintain the rest of the protocol, seriously. They can't resolve the practicalities of patients' lives.
I'm also taking dust mite immunotherapy and assumed this article applies to me.
As a giant confounding effect, it seems that allergy immunotherapy might work, at least in part, by convincing your body to make large amounts of IgG antibodies to the allergen, and IgG antibodies are in the “kill it but don’t sneeze at it” category, which isn’t same thing as having your T cell population tolerate the antigen.
Doctor’s have a wide discretion and often get things wrong. But in your case, that’s not what happened. If anything your doctor actually got it right either by chance or intuition.
Autophagy is increased during fasting, it usually takes 3 days of water fasting to fully ramp up to its maximum, so no food overnight might just slightly start it up.
I watched a youtube video of guy who did low carb and fasted at least 24h before and after chemo (or even 48h, forgot which) and he didn't experience the negative side effects of chemo as much.
apparently it was prospective and randomized. I’m a little shocked by the effect size.
I don't really care at that point what their conclusion says, because I have no idea how to interpret the statistics in a theoretically sound way now.
Administering immune system related drugs in the morning improves success rate. This is because the immune system is more receptive in the morning, due to evolutionary adaptation. The authors even seem to have isolated the gene sequence that leads to the "sensor" which generates the necessary "data" for the immune system to optimize on.
Really cool research imo
> this paper was not a retrospective study of electronic health records, it was a randomized clinical trial, which is the gold standard. This means that we’ll be forced to immediately throw away our list of other obvious complaints against this paper. Yes, healthier patients may come in the morning more often, but randomization fixes that. Yes, patients with better support systems may come in the morning more often, but randomization fixes that. Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that.
The same thing it means in every context: that (with enough samples) you can control for confounders.
I think you're correct that randomising patient assignments doesn't control for provider-side confounders. Curious if the study also randomised nursing assignments.
Whether or not they controlled for nurse-alertness is something you'd have to read the paper (or assume the researchers are intelligent) for.
There is also the mechanistic side: if you have lots of plausible mechanism for what's going on, and you can detect indicators for it that don't seem to correlate with nurse alertness, that's a vote against it mattering. Same if you have of lots of expertise on the ground and they can attest that nurse alertness doesn't seem to have an affect. There are lots of ways, basically, to reach pretty good confidence about that, but they might not be as rigorous as randomized assignments can be.
How does randomization fix that?
How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?
Given the highly-evident strong circular nature of the body, a hypothesis that it has something to do with that seems highly likely, certainly worth following up on.
Irrelevant to this study given randomization.
Believe they are being treated like robots. Maybe even literally like gears rented by the hour, not even robots.
This said, I am inclined to believe that this isn't a major concern for chronotherapy studies, since I haven't yet seen it being raised in any paper yet as a concern and the results seem far too strong to blame entirely on 'night nurses make more mistakes'. Fully possible that that is the case! I just am on the other side of it