🕹️ Good write up in today’s FT about Esoteric Ebb, a fantasy RPG which seems to be heavily influenced by Planescape: Tornment, Disco Elysium and Terry Pratchet’s Discworld. Sign me up! Mentioned at the end is Type Help, a free-to-play text adventure that is quite unlike any work of interactive fiction I’ve seen before. Recommended.

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:

• Netflix, which I tend to picked on even as I commend its better offerings. Turd to diamond ratio is still too high, and with the most recent price increase it is not worth it any more.
• Paramount+, because there are better things to do in one’s life than watch Star Trek reruns.
• Disney+ would have been a cancellation as we rarely ever watch it. But for some reason we have been grandfathered into the Disney+/Hulu/ESPN+ 4K plan for $80 per annum and at that price it is worth it to have Gravity Falls available at a moment’s notice.
• All iOS weather apps, because my weather-related needs just aren’t that sophisticated and the default app serves them fine, thank you very much.
• Hookmark, previously known as Hook, a MacOS productivity app that (1) pissed me off by brandishing the tag line “Buy Once, Own Forever” even as it kills you with notifications that the new version 3.2.1.3.2.5 is out and you need to pay $30 for an “Updates license” all while (2) I am trying to move away from MacOS anyway. Yes, technically this is not a subscription that needs canceling but the toughest attachments to part with are those that exist only in my mind (see also: Tinderbox, DEVONthink, OmniFocus, MailMate, etc.)
• Epsilon Theory, a more esoteric platform which never quite recaptured the time they first grabbed my attention.

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.

• Monopolized by David Dayen, which Cory Doctorow recommended in response to my account from last week of the medical billing/phone scam rabbit-duck. Doctorow wrote about the book in more detail back in 2021 and yes it is now on the pile as is everything else below.
• The Credibility Crisis in Science ⊕ ↬ Joel Hamill by Thomas Plümper and Eric Neumayer, and if the subtitle “Tweakers, Fraudsters, and the Manipulation of Empirical Results” whets your appetite there is an excerpt available in Nautilus.
• The Art of Manliness by Brett and Kate McKay, who have had a blog of the same name for more than a decade, so it is a true mystery why an article in The Dispatch about the “gentlemanosphere” ⊕ ↬ Reader John chose to highlight overtestosteroned almost-douchebags such as Scott Galloway as the anti-manosphere crusaders rather than McKay. Haha, I’m joking, of course it’s not a mystery: Galloway gets more clicks, taps, swipes or rather the preferred method of interaction is nowadays. He also has a new book out, to which I shall not link.
• The Oxford Book of English Verse edited by Christopher Ricks, which someone recommended on The Honest Broker Podcast, a show that combines some of my least favorite things about this decade: Substack and using the word “podcast” to describe a video of two men talking. Still, the transcript makes for good reading and the book seems something worth keeping at the bedside, at least aspirationally.

📚 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!

• Bayesian Workflow, a new book from Andrew Gelman et al, coming out in June. Here is Gelman’s announcement and here is the book’s web page.
• The Alba Madonna, ⊕ ᔥ Tyler Cowen a painting of Raphael’s at the National Gallery of Art, which you can examine in detail on their website.
• The Classical Station, ⊕ ᔥ William Parker a no-nonsense, no-tracking stream of human-selected music. Here is their daily playlist.
• just the fracking QR code, ⊕ ᔥ Jahir Fiquitiva on Mastodon a no-nonsense, no tracking website that will give you the QR image for any text, file or hex code you desire.
• Jellyfin, a home media server which resembles Plex before it was enshittified. Note that (1) I am yet to try it out and (2) the person whom I first saw mention it does not in fact endorse it.

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.