12 ms·
Administering immunotherapy in the morning seems to matter. Why?
- pmlnr 1y agoBody meridian clock, that's why.
- zevets 1y agoThis is bad science. Patients schedule when they go to immunotherapy appointments. People who go in the morning are still working/doing things, where once you get _really_ sick, you end up scheduling mid-day, because its such a hassle to do anything at all.
- vhanda 1y agoFrom the article - > 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.
- tines 1y agoWhat does randomization mean in this context, and why does it fix those problems?
- NhanH 1y agoPatients are assigned the time for their visits. The time itself is randomized
- ajkjk 1y agohttps://en.wikipedia.org/wiki/Randomized_controlled_trial https://en.wikipedia.org/wiki/Randomized_controlled_trial The same thing it means in every context: that (with enough samples) you can control for confounders.
- tines 1y agoSupposing that patients did better in the morning because, say, the nurses were more alert, no matter how many samples you take you'll find the patients do better in the morning. How does "more samples" help control for confounders rather than just confirm a bias?
- JumpCrisscross 1y ago> How does "more samples" help control for confounders rather than just confirm a bias? I think you're correct that randomising patient assignments doesn't control for provider-side confounders. Curious if the study also randomised nursing assignments.
- ajkjk 1y ago"more samples" is not what controls for confounders. Controlling for confounders is what controls for confounders, which you can only do with enough samples that you can randomize out the effect of the confounder. Whether or not they controlled for nurse-alertness is something you'd have to read the paper (or assume the researchers are intelligent) for.
- tines 1y agoI guess I'm asking, how do you randomize out the confounder in this case.
- ajkjk 1y agoI imagine that that particular confounder is not possible to eliminate via randomization. Perhaps you collect a bunch of data on nurse awakeness--day shift vs night-shift, measuring alertness somehow, or measuring them on other activities known to be influenced by alertness--and then ensure your results don't correlate with that. 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.
- kelnos 1y agoPatients in the study are randomly assigned to the early group or the late group. They don't get to schedule their own appointments for whatever time of day they want.
- tines 1y agoHow does this control for the "alert nurses" variable? In that case, patients would do better in the morning, regardless of the patient.
- anigbrowl 1y agoWhy would you assume nurses are scheduled on a 9-5 basis?
- simmerup 1y agoWhy do you think you're going to poke holes in a research article when you've clearly only just heard of the concept and havent even read the article
- tines 1y agoIf I thought I could poke holes in the research, I wouldn't be posting on HN. I'm asking questions to learn because obviously I don't understand :)
- d_tr 1y agoBased on these graphs and the differences in outcomes they show, you are not talking about "alert vs less alert" nurses but about "nurses doing their job vs nurses basically slowly killing dozens of patients".
- leereeves 1y ago> Yes, maybe morning nurses are fresher and more alert, but, again, randomization fixes that How does randomization fix that?
- finnh 1y agoexactly. that one clause casts doubt on all the other reasoning; randomization controls for patient selection bias but not diurnal clinic performance
- phanimahesh 1y agoIt would if the clinic is a controlled setting and they can control when the nursing shift begins.
- deleted 1y ago[deleted]
- gus_massa 1y agoHow many dose this treatment has? How many between them? How many patients dropped out? (Or requested a schedule change) Do they count like live or dead?
- vibrio 1y ago"Forced to throw away" biases is strong. If run well, RCTs surely help manage potential biases, but it does not eliminate them. The slides saw available on X-itter didn't show a Consort diagram (accounting of patient count between screening and endpoint) or the balance of patent characteristics between the arms. This seems to be a single site study, which is significant caveat IMO. The lack of substantial mechanistic explanation, and alleged study redesign mid-stream are also caveats. All that said the reported effect is very large, and I'd like to see a more detailed reporting and analysis. If the effect that size is real, it should be able to be found in some relatively quickly retrospective studies (yes, many caveats there, but that could probably provide very large numbers rapidly in support of the RCT).
- majormajor 1y agoI always have seen mid-day appointments as also a luxury for those doing well (at least professionally/financially). If you have to go first thing in the morning, it's often because your boss wants you in relatively early and won't let you take time mid-day. If you're in a position where you can go in at 2PM and not have to sacrifice sleep to do so, that feels healthier. 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.
- detourdog 1y agoI can schedule appointments whenever I want. I'm an early riser and prefer my appointments first thing in the morning.
- JumpCrisscross 1y ago> mid-day appointments as also a luxury for those doing well Irrelevant to this study given randomization.
- pbhjpbhj 1y agoSurely your boss legally has to let you attend a health appointment? Though they might not have to pay you. That seems like a very basic workers right, the sort of thing you'd have a general strike over if it didn't exist??
- mjevans 1y agoThe most vulnerable, at least among those who have a job at least, often have the most draconian restrictions on when and what they can do. Believe they are being treated like robots. Maybe even literally like gears rented by the hour, not even robots.
- munchler 1y agoThe appointment schedule was randomized, so your objection is incorrect.
- abhishaike 1y agoWriter of the article here: randomization fixes most of this, but the other commenters are correct in that doesnt fully account for the clinic performance (e.g. nurse performance, which does dip during the night according to the literature). I previously thought it wasn't a major issue for clinical trials, since a separate team independent from the main ward are giving the drugs, but there isn't super strong evidence to support that. I will update the article to admit this! 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
- deleted 1y ago[deleted]
- rendaw 1y agoI'm doing CedarCure. You're required to not exercise or bath/shower for 2h after taking, which is fairly difficult in the morning, so I asked the doc if I could do it in the evening instead (despite explicit instructions to do it in the morning). The doc said it was fine, confirmed by the pharmacist. 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...
- detourdog 1y agoI looked up CedarCure and what I found is that it is a pesticide. What is the treatment about?
- rendaw 1y agoIt's an immunotherapy drug for cedar pollen allergy.
- iamtheworstdev 1y agolooks like a sublingual immunotherapy treatment for allergies to japanese cedar pollen.
- tines 1y agoOP is an insect going in for assisted suicide.
- annoyingnoob 1y agohttps://synapse.inc/medicine/9101/ https://synapse.inc/medicine/9101/
- justsomehnguy 1y agoThere is always an option what taking it in the evening is magnitudes better than not taking it in the morning at all because you skipped it because you need a shower. Always remember what you are just an another patient with your own quirks.
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- jmward01 1y agoI wonder if other basic processes could be at play here like when patients go to the bathroom. If you do this in the morning they may be more likely to not need that for a while while in the evening they may do that immediately. I'm not saying this is the mechanism, just pointing out that there are a lot of timing dependent things in a person's schedule that could be a factor here. It is a great thing to point out though. I hope a lot more research goes into the idea of timing and integrating medication into a schedule most effectively.
- HexPhantom 1y agoWe tend to treat the body like a static system when it's actually dynamic across the day
- unnamed76ri 1y agoI used to be on a chemo drug and had to take folic acid every day to stop it from doing bad things to me. 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.
- tomcam 1y agoThanks for sharing, and I’m very glad you are here to discuss it.
- HexPhantom 1y agoHow many side effects people just accept because no one thought to tweak the schedule
- cenamus 1y agoAnd to think about how often such things are figured out individually, but go unnoticed, because there's basically 0 chance for the average person to get anyone to do a study on it.
- hypercube33 1y agoMy guess on some of this has to do with a few things. Hormone levels vary throughout the day along with immune system activity; My allergies are always worse in the morning than the day. I'm sure time is a huge component in a lot of medical things but I haven't personally seen any studies on this. Most people also fast at night (sleeping) and are less physically active etc etc.
- unnamed76ri 1y agoI did make sure to bring it up to my doctor in case the idea could help anyone else.
- Laaas 1y agoLight affects us deeply. Very probably true for more than immunotherapy.
- NotGMan 1y agoPerhaps it's due to overnight fasting, that people in the morning don't eat yet/as much? 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.
- levocardia 1y agoHazard ratio of 0.45 seems implausibly high, especially when it's just the exact same treatment dichotomized to before/after 3pm. My money is on something other than a real circadian effect: either the result of a 'fishing expedition' in the data, or some other variable that incidentally varies by time of day. Maybe breaking randomization, leaving the drugs out for too long at room temp, etc. If you really believe this is an important and biologically plausible effect it should be a top candidate for a replication attempt.
- trhway 1y ago>some other variable that incidentally varies by time of day. 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) .
- levocardia 1y agoAM/PM glucose differences are probably going to be swamped by mundane stuff like who has a snack before treatment vs. who doesn't. Are you not supposed to eat before immunotherapy? If so, maybe (non)compliance with that requirement is what's underneath.
- egocodedinsol 1y agoHere’s a link to the abstract: https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.8516 https://ascopubs.org/doi/abs/10.1200/JCO.2025.43.16_suppl.85... apparently it was prospective and randomized. I’m a little shocked by the effect size.
- munchler 1y agoThis paper was not a retrospective analysis, it was a randomized clinical trial.
- egocodedinsol 1y agoYeah I’m checking - I saw several other oncologists suggesting song a separate discussion.
- raylad 1y agoMy 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.
- BDGC 1y agoIf you’re interested in circadian biology, which underlies chronoimmunotherapy, please check out UCSD’s BioClock Studio. We create tutorial videos and other media to teach circadian biology concepts: https://bioclock.ucsd.edu/ https://bioclock.ucsd.edu/
- owenthejumper 1y agoSicker patients get emergency treatment in the hospital in the afternoon while healthier ones in the morning in the clinic
- Spooky23 1y agoCancer treatments typically don’t happen in an inpatient setting.
- owenthejumper 1y agoOf course they do
- anthuswilliams 1y agoThe article is reporting on randomized clinical trials, which are not subject to this dynamic.
- georgeburdell 1y agoNot a medical doctor. Does this also have implications for other immunotherapy like allergy shots?
- parsabg 1y agoI wonder if the same would also be true for immunosuppressants administered for autoimmune conditions. Given they mostly interact with the signaling pathways, I guess in theory they should also be more effective in the morning if there is more immune cell activity going on.
- more_corn 1y agoBecause the immune system sleeps at night and wakes up in the morning?
- Kiyo-Lynn 1y agoI once accompanied a family member through immunotherapy. The treatment times were mostly arranged by the hospital, and the doctor suggested doing it in the morning. We just thought it was to avoid the afternoon rush. Looking back, though, they really did seem to feel better with morning treatments. Now I realize the timing itself might actually affect how well it works. I really hope that in the future, doctors will consider not just the drug and the dosage, but also when it’s given.
- Spooky23 1y agoThey do - for metastatic melanoma, the goal is before 4:30, which is linked to higher survival rates.
- Kiyo-Lynn 1y agoI didn’t know there were already examples like metastatic melanoma where the timing is clearly defined. It makes me wonder if other treatments could also benefit from getting the timing right. Thanks for sharing this. I’ll definitely look into it more.
- EricPhy 1y ago“Let’s pretend you have very early-stage cancer. The dendritic cells are in their normal cycle of desperately presenting tumor fragments to T cells, the T-cells rightfully getting upset, activating themselves, and going off to hunt the cancer. But cancer simply shuts them down by expressing an immune blocker protein: PD-L1. In response, the T-cell mostly shuts down, wanders back to the lymphatic system, and gets a little bit more ‘exhausted’. It believes that it activated itself for no reason, and thus will require a much higher bar for doing anything else in the future. The more times this occurs, the more exhausted the T-cell becomes, the more unwilling to ever activate again. In the limit, it will simply kill itself. Hence why you need immunotherapy to revitalize these cells!” That’s a powerful analog for depression and burnout in humans.
- cluckindan 1y agoAnd not necessarily just an analog, given how there is an immune component to stress.
- agumonkey 1y agoYeah, so many things use the same memory response curve to adjust their behavior, but that model can fail rapidly in these conditions. Very interesting to read though.
- HexPhantom 1y agoIn a way it feels like we're scratching the surface of a new layer of treatment optimization
- OrderlyTiamat 1y agoThey changed the study target effect (which hour range), design (interventional vs observational) and inclusion/ exclusion criteria multiple times. 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.
- Noelia- 1y agoA while back, a colleague told me his doctor always scheduled his immunotherapy infusions for the morning, saying it would be more effective. I thought it was just something they said, but seeing all this new data, I’m realizing there’s actually real science behind it.
- aitchnyu 1y agoIf a hospital cannot serve everybody in the morning, should they create a dorm with only artificial light that has sunrise at 12 pm and sunset at 12 am to shift circardian rythms?
- s1mplicissimus 1y agotl;dr 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
- yoko888 1y ago[dead]
- ImHereToVote 1y agoFasted state?