Tax Day was a good kick in the rear to clean up all the recurring payments that have accumulated over the years. Here are a few notable cancellations:
So with all of that deadweight removed, I felt that I could splurge on a Digital+Print subscription to Nautilus, an even more lay audience-friendly version of Quanta Magazine. Both of those are, of course, wildflowers growing out of the compost pile that was Scientific American. Thus Nautilus joins the Financial Times as the only print editions we subscribe to, all other magazines that come in the mail being hoisted on us as members of various medical societies.
Apart from looking like he has just been on the losing end of a fistfight, and having occasional bouts of nausea, Ben Sasse seems to be doing as well as someone recently diagnosed with metastatic pancreatic cancer possibly could. Both the nausea and his face peeling off are because of daraxonrasib, a new drug which targets KRAS G12 mutations which are common in many cancers but are found in most pancreatic ductal adenocarcinoma (PDAC). As a reminder, PDAC is the one that Steve Jobs did not have, the one that has the dubious distinction of being both the most common and the most lethal cancer of the pancreas.
Well, daraxonrasib seems to be doing its job and doing it well, based on a company press release. Remember, most press releases should not count as evidence for anything. This particular one, however, is worth reading because it is (1) for a randomized controlled trial with (2) a “hard” endpoint of overall survival OK, putting my pedant hat on, the pre-specified co-primary endpoints are progression-free survival (PFS) and overall survival (OS) in the RAS G12-mutant population. What is reported in the press release is only OS in the “intent-to-treat” which is to say both G12-mutant and wild type populations, which was a secondary endpoint. A bullet point at the beginning says that all primary and key secondary endpoints were met, so why not report both? Probably because one looked better than the other, but would it not be a tad suspicious that a less targeted population did better than the more targeted one? But this is just speculation, let’s see review the actual data once they come out. which will (3) be presented at the ASCO annual meeting, I imagine as a plenary talk, in early June of this year. The thing to look for there will be informative censoring, in particular early censoring of frail participants — the ones more likely to die early of their disease — who were randomized to receive daraxonrasib but then withdrew due to the “manageable” toxicity of a melting face. The fact that there are no participant numbers reported at all in the release makes me suspicious, though information on the number of patients enrolled is readily available: 501. That’s a lot of patients!
The company is certainly feeling optimistic: they have already received a National Priority Voucher from the US FDA and will now submit a New Drug Application. Kudos and congrats for designing and testing a working drug without using AI, because to read both professional and lay media the past two years it is a miracle there were any drugs being discovered until Large Language Models came along.
Yes, I had to invoke AI, because it is becoming exceedingly common for people to give algorithms credit where it is not due. This is what Tyler Cowen wrote yesterday about pancreatic cancer research:
AI and the pancreatic vaccine. More testing is needed, but there is a reasonable chance that we have a good treatment for pancreatic cancer, and AI was instrumental in that. It is mRNA as well, so a double burn on the haters.
The link is to a post on X by one Rotimi Adeoye, a “contributing opinion writer @nytimes” (one guest essay as of today which is one more than I have so congratulations, I guess?) who in true X fashion superimposed a screenshot from an uncredited journal abstract over someone posting a link to an NBC news article about the updated results of a phase 1 trial of an mRNA vaccine for pancreatic cancer. For those not keeping track, you are right now reading a blog post about a blog post about a retweet of a tweet about a news article based on a press release. You’re welcome. These were presented yesterday at the annual meeting of the American Association for Cancer Research but were hinted at in a press release (?) from Memorial Sloan Kettering, where the vaccine — generic name autogene cevumeran which rolls right off the tongue doesn’t it? — was being tested.
Remember how a few paragraphs above I had implied that you should ignore most press releases? Well, news on academic websites should rank even lower as no one there has to answer to the SEC. The primary study was great for what it was, a first-in-human trial with laboratory endpoints meant to test whether the participants’ immune system responded at all to the vaccine. And it seems that it did, as shown in not one but two papers in Nature published two years apart. The number of original participants, all of whom had early-stage, freshly resected and otherwise untreated PDAC upon enrollment, was 19. Three of these did not make it to the vaccine as they had progression, died, or had toxicity from adjuvant chemotherapy before being dosed. Chemotherapy? Yes, in addition to the vaccine everyone also received “adjuvant” (meaning: there to “clean up” any residual cancer after surgery) chemotherapy (FOLFIRINOX, not for the faint of heart) and immunotherapy (atezolizumab which is in comparison to the chemo a walk in the park but even that has its side effects). There was no control.
Of the 16 participants, 8 were “responders” to the vaccine as measured by some highly sophisticated laboratory tests — not that the patients would care what their blood work showed — and in 7 of those the cancer hasn’t come back for 3 years as noted in the follow-up Nature paper or for 4-6 years as noted in yesterday’s update. This compares to 2 of 8 who were “non-responders” to the vaccine.
If you don’t have your calculator handy let me do the math for you: 9 of 16 patients, or 56.25%, with newly resected PDAC who received chemotherapy, immunotherapy and the vaccine were still alive more than 3 years after treatment. You may not know this, and I didn’t until I looked it up just now as it has been a while since I have treated patients with newly diagnosed early-stage pancreatic cancer, but the median OS after (modified) FOLFIRINOX alone in a recent large, randomized Phase 3 trial was 53.5 months, with 43.2% of patients still alive 5 or more years. Did the addition of atezolizumab and the vaccine change anything? I can’t tell and neither can anyone else until there is a randomized controlled trial, which isn’t to cast shade on the investigators — kudos to them as well for a successful first-in-human study — but let’s curb our enthusiasm.
So we have some updated results from a tiny trial that didn’t really move the needle one way or another, and yet Cowen et al. feel the need to push AI into the narrative. To be clear, there is absolutely no mention of LLMs, machine learning, algorithms or artificial intelligence of any kind anywhere in the autogene cevumeran literature. Granted, it is a “personalized” vaccine, meaning that every potential participant had their tumor sequenced and up to 20 vaccine targets identified among the newly mutated proteins. I am sure there was a lot of computation involved. But not every sophisticated computer analysis is AI, let alone an LLM, so I truly don’t see how they could legitimately be brought into the conversation.
And in case you were wondering, no, the screenshotted abstract did not in fact back up Adeoye’s claim. Best as I can tell this was the paper in question, a speculative review article in an obscure journal written by a Shanghai-affiliated group of authors who had nothing to do with BioNTech whose purpose was to be a never-looked-at reference for a false claim, that “AI played a critical role in advancing the vaccine”. Anything for the clicks, am I right?
Adeoye’s behavior was regrettable but Cowen’s is detestable, especially when paired with his look-at-the-sheeple attitude towards humans. The linked to article from Cowen is particularly wrongheaded if you realize who the Luddites really were and that the label should in fact be a positive one. Cory Doctorow had warned about AI companies over-promising their capabilities for a short-term gain. But they don’t really need to: there are plenty of useful fools willing to promise on their behalf, giving it credit even where there is none.
📚 Finished reading: Do Androids Dream of Electric Sheep? by Philip K. Dick, so I now have no choice but to watch Blade Runner for the fourth or fifth time. I suspect that — much like with the novel — quite a few parts will “hit different” this time around.
Infinite Regress is not a professional outlet yet even this here half-brained bozo knows better than to mix fonts in a single word. They should have shaved off the “ć” to a “c” if their house headline typeface didn’t have the right diacritic, but then why doesn’t it?
And hey, congrats to Denver!
As seen in the restroom of our favorite non-seafood restaurant in all of Eastern Shore, The Irish Penny Pub and Grill in Salisbury, MD. It’s the perfect pit stop on the way to the beach, but really I’d drive 2.5 hours from DC just for their boxty.
For reasons that will soon become apparent, I would like to share with you a joke I heard back at medical school. I will remind you that this was in Belgrade, Serbia in the early 2000s, but the joke would apply to any Serbian institution of higher education, or indeed any place anywhere in the world that uses oral exams I have heard these called viva voce in the US, which is a bafflingly cheerful-sounding name for a rather traumatic ordeal. to determine the final grade. Please also bear in mind that I am not the best at telling jokes.
Anyway, here it is. A not very well prepared student comes in for his Anatomy 1 exam with a rather erratic professor (the joke had the actual name, which I am sure changed from time to time and from school to school). While sitting in front of the office waiting for his turn, a teaching assistant (again, named) approaches him. “Look”, the TA says, “I know he can be tough but for 100 euros things would go a lot easier for both of you. I’m going into his office now so if you have enough with you I can pass it on.” It so happened that the student did have a fresh 100 euro bill with him, which he gave to the TA, who then knocked on the door, spent a few minutes in the office, then came out with a smile and a nod. With newly boosted confidence, the student did better than he could have hoped for and got a 7 (on a 5 to 10 scale). Beaming with pride for his academic savvy and mental fortitude, he winks at the TA hanging around in the hallway. The TA winks back.
So when the time came for Anatomy 2 Technically, there was no “Amatomy 1” and “Anatomy 2” but rather a mid-oral exam you had to do after the first two semesters where you got drilled about everything but the central nervous system, followed by the final oral exam in which everything was in play. Fun times., our student was even more confident and less prepared, and by now you should know where this is going. Same professor, same hallway, same TA coming in with an offer for the privilege to pay a 100 euro lubrication fee. Alas, the professor was in a foul mood that day and flunks the student within 10 minutes. Crestfallen, the student slouches out of the office and sees the TA. “So sorry about that”, says the TA while handing him back the 100 euros, “but you were so bad that there was no chance he could let you pass.”
The joke, if you can call it that, is that the professor was psychotic but not corrupt, and that the TA was playing a game of chance. If it works it works, if not, well, there is always the money-back guarantee. It is as close as you can get to a victimless scam.
A phone call my wife received this morning reminded me of the scheme. It was from someone presenting as staff from the Johns Hopkins billing department. Apparently, there was a balance past due, back from November of last year. This was only a courtesy call, you see, but would you like to pay now or set up a payment plan, to avoid it being sent for collection?
Between the six of us we get about two dozen Explanations of Benefit each quarter. I may not be diligent about looking at every line item, but if there is one thing our insurance company helpfully provides even without logging in to the portal and opening the PDF it is the amount owed. Now, if my wife and I were inundated with work the way we usually were something could have slipped through the cracks, but I was on paternity leave with more time than usual to deal with the overhead of living in the United States so I was pretty sure there was nothing we could have received from insurance that we would have missed.
Except for a pile of snail mail on our dining room table, which I collect about once per week. And there, in an envelope addressed to my wife, was an account statement from Hopkins dated last week — due early next month — that said that we did indeed owe just shy over half a grand for hospital services rendered last November.
This was the first we had ever heard about owing for these particular services, rendered in an in-network facility, performed by in-network physicians. And was that not a curious sequence of events, an early morning phone call urgently asking you for money you didn’t even know you owed until, at best, just the week before? I didn’t want that particular loose thread hanging over me on Tax Day of all days so there I was, HRA card in hand, ready to settle the balance online, until my wife who is as wise in the ways of health insurance and billing as she is in the ways of shopping asked me to cross-check the Hopkins statement with the insurance EOB before I did anything rash.
What a good thing I did, as they did not match. If you are lucky enough not to have to deal with American health care, this is how billing works: hospitals have a list price for their services which they pull out of thin air. Insurance companies have their own opinion about what those services are worth, and a hospital being “in-network” means that they have agreed on the insurance company’s price while “forgiving” the rest. On the hospital bill this will be the “insurance adjustment”. Well, the adjustment our insurance said they negotiated and what was shown in the Hopkins statement differed by exactly the amount Hopkins was now asking from us, which as an in-network hospital they were not allowed to do.
So now it was me on the phone calling the Hopkins billing department, asking about the charge, the person on the other end of the line checking — on a 15-minute muzak hold — what was going on, not finding out, promising a call back in 5 to 7 business days and not to worry about the collection because we will get to the bottom of this mysterious error (if it is an error at all, let’s wait and see) that the hospital made, happens very rarely, practically never, always in the hospital’s favor. I look forward to receiving a voicemail, 5 to 7 business days from today, telling me that the magnanimous Hopkins billing department staff has forgiven all our transgressions and that our balance was zero.
Back when there was such a thing as guidance on conflicts of interest for federal employees, it was drilled into and onto us that even semblance of impropriety, what social network warriors would tag as not a good look, was to be avoided at all costs. It does not matter if you did or did not mean to pick this contractor because your spouse works there — they may be the best company in the world for the job for all we care — you should not be involved in the decision. I agree with this now-antiquated viewpoint and propose extending it to scammy behavior or large corporations. It doesn’t matter whether you used a fake charge on a late bill to threaten collection while offering a quick solution with the express intent to defraud or if an unfortunate series of events led to only the appearance of a scam: it is not a good look. One that, unlike our fictional teaching assistant’s, can and does have real victims.
🍿 It Chapter Two (2019) was a tad too long and a bit of a drag, because adulthood is a drag and we are seeing the kids all grown up. What would have worked much better is if the modern-day scenes were interspersed with the 1980s so that we learn about the story as the adults remembered it. Brilliant idea, I know.
Having switched to Linux for 90% of my computing, I realized Emacs could cover much of those 90%:
And for all my kvetching about how ugly Emacs can be, this was in fact a me problem and not an Emacs problem. It took 8 lines of code and downloading some decent fonts for things to look much better.
Microsoft’s Windows Office Copilot web apps cover almost everything else. Alas, not absolutely everything:
Which is to say, expect a few more of these updates on the software side. Hardware will have to wait.