A Wrinkle in Time 👎

So much wasted potential in this one. It could have been a great movie for both children and adults, a Labyrinth for the age of CGI and social justice. Instead, it’s a confused, hurried mess in which lots of Stuff happens for no good reason; a Michael Bay extravaganza for your middle-schooler. My daughter (6) liked it, but even she questioned a major plot point. “But, why did X become evil, daddy?” I’ve no idea, Honey, and I’m not sure the screenwriters gave it much thought either.

Such is the faith of many book adaptations; this one even more so, having had to pass through the Disney committee wringer. I haven’t read the book(s? That’s how much I know about the potential franchise) but I’ve read and watched enough fantasy to know that 1) your made-up world needs to have rules, and 2) if you break them, it better be for a good reason. The few week rules set in the Wrinkle’s first half are promptly broken at the half-time, with no explanation and nothing to replace them. Instead you get a holodeck of a planet, where anything can happen: hurricane in a haunted forest turns into a Stepford wives cul-de-sac turns into a crowded beach, and no there is nothing connecting those dots.

Which is too bad — each one of those scenes would’ve made a good episode for the second season of the unmade Wrinkle TV show, perfect for Disney’s new streaming service. Such a waste.

Directed by Ava DuVernay, 2018

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The three flavors of interleukin-15

One thing I realized at SITC this year was that not many people know (or care?) about the difference between the IL-15s now being tested in trials. There are: the recombinant human (rh)IL-15, the IL-15/IL-15Ralpha heterodimer (hetIL-15), and ALT-803, the “super-agonist”. You’re better of reading a more comprehensive review, but some highlights are below.

  • The simplest, oldest, and seemingly most potent is the plain vanilla rhIL-15.
  • Four dosing strategies have so far been tested: bolus (too toxic, published), subcutaneous (OK, about as good as ALT-803 in increasing NKs and CD8+ T cells, also published), 10-day continuous infusion (the most potent, but who wants to sit in a hospital for 10 days, should be published soon), and a 5-day infusion (same 40-fold increase in NK numbers in half the time! presented at SITC)
  • None of the patients in any of the regimens had a RECIST response, but most mounted an impressive lymphocytosis, leading to several planned combination trials
  • It is available for investigator-initiated studies through CTEP. They will also give a few vials for preclinical studies.

  • Novartis owns hetIL-15, and is running the phase I alone and in combination with their anti-PD-1. Nothing published, but I’ll have more to say about it next year.

  • ALT-803 is an IL-15/IL-15Ralpha heterodimer blessed with a single point mutation which confers upon it both increased binding to the common gamma chain, and validity to the claim of new IP.

  • It is the only one shown to have efficacy as a single agent (though not in solid tumors), and the only one to be part of a published and/or presented combination (with nivolumab in NSCLC, and with rituximab in FL).
  • What’s presented so far makes it less potent than rhIL-15 in increasing cell counts, but more convenient to give: via once-weekly subcutaneous injections for an 8-fold increase in NKs.
  • The company, Altor Biosciences, had been fairly open to IITs — one of them is currently open at NCI’s GU Malignancies Branch — but maybe not so much since being acquired in August 2018 by NantCell, a Patrick Soon-Shiong company.

There’s more, of course, but I’ll end instead with another plug for our review of cytokines in cancer therapy.

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Yes, CAR-NK cells are exciting (as exciting as they can get after a phase I single-center yet-to-be-published trial)

For more than a year now, the big names of CAR-T-cell world have been sharing their excitement about the potential of NK cells to be a much better CAR carrier. There are many hypotheses about why that would be, but you can hypothesize all you want until you give the product to humans. PET scans can lie, but not nearly as much as your average transgenic mouse model.

Well, anti-CD19CAR-NKs have now been given to at least 9 humans, as reported by Dr. Katy Rezvani from the MD Anderson Cancer Center at the SITC Annual Meeting a few days ago, and what she reported was as good as it gets for a first-in-human trial of a new gene/cellular therapy. The five takeaways:

  1. Off-the-shelf cord blood-derived NK cells carrying a CAR can safely be given to humans without HLA-matching. This could decrease both cost and time to treatment.
  2. None of the nine patients had cytokine release syndrome or neurotoxicity. After all, NK cells aren’t big cytokine producers.
  3. Six of nine patients had a complete response and one more had a partial response for a 77% response rate.
  4. One of those CRs and one PR were patients with CLL and Richter’s transformation, another CR was in a 70-year-old with double-hit lymphoma, and yet another in a patient with CLL and 17p deletion. These are tough diseases.
  5. Contrary to what was hypothesized about NK cell longevity, the CAR-NKs persisted for up to six months after treatment. We still don’t know what that means for CAR-Ts, let alone CAR-NKs, but I consider it a win each time experiment refutes theory.

So yes, I am also excited about CAR-NKs. However:

  1. This is an unpublished, non-peer-reviewed, single-center experience. There could be research hospitals out there giving CAR-NKs with results too horrible, or just too middle-of-the-road, for early promotion.
  2. CLL is notoriously difficult to stage, and five of the nine patients had CLL. Consider the MURANO trial (Venetclax-Rituximab combo fo relapsed/refractory CLL), in which the investigator-assessed complete response rate of 26.8% turned to 8.2% on independent review committee assessment.
  3. Follow-up is limited and it is too early to know the response duration. Long enough to get to an allo transplant, at least?
  4. The same limitations in target availability we have in CAR-T cells apply to CAR-NKs. It has to be a surface antigen with limited to no expression on normal cells. There aren’t too many of those, particularly in solid tumors.

Still, kudos to Drs. Rezvani, Shpall, and others at MD Anderson. This is as good as it gets at this early stage.

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Ending medical reversal

The first thing I picked up after taking the hematology boards was this gem from Chicago’s medical royalty (Adam Cifu) and everyone’s favorite oncologist (this is of course a joke — you know that people hate your guts, Vinay).

I didn’t, and still don’t, care much for the title. It is ambiguous: if medical reversal means overturning an established practice that was based on weak to no evidence once stronger evidence comes along — usually in the form of a (multi-center, blinded) randomized controlled trial — why on earth would you want to end reversals? Well, the book is about how to stop those kinds of practices from becoming established in the first place, which would indeed end medical reversal, but an easier way to stop them and one that would be endorsed by most of industry and many researches would be to just not look. “Ending Medical Reversal the Hard Way” is therefore a more appropriate name.

Title aside, I agreed with pretty much everything they wrote, from reforming medical education, through stopping direct-to-consumer marketing and direct-to-academic (not their words) payments, to having more people participate in (simpler, cheaper, and fairer) randomized trials. I enjoyed their honesty and clear style, and wished my medical school had at least a passing resemblance to the one they proposed (if you thought US medical education leaned too much on basic science-oriented and was heavy in professorial mechanistic proclamations, try the average European med school). Granted, I work in a federal research hospital and focus on some of the rarest of the rare diseases; but that only makes me shake my head in disbelief more when my colleagues who specialize in breast or lung cancer, not to mention coronary artery disease and diabetes, randomize enormous numbers of patients to search for minute differences in surrogate outcomes.

Written by Vinayak Prasad and Adam Cifu, 2015

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Stubborn Attachments

This is as close to a “Rules for Life” book as we’ll get from Tyler Cowen, and if you’ve listened to his podcast or followed his blog what’s inside won’t surprise you — but it will make you think. Which is good: surprise is overrated anyway, and things that depend on it don’t do well on re-reading/watching/listening. I’ll be coming back to this one.

Cowen argues that growth is good even when it doesn’t benefit everyone all the time. There are things that can grow that you can’t measure (like happiness, life satisfaction, health, culture, feeling of superiority [I may be misremembering some of these]), so don’t focus on wealth only but instead on Wealth Plus. Also, distant future is just as important as the near future, so don’t sacrifice long-term prospects for short-term gains. Speaking of future, we can’t predict it, so even though tiny decisions can influence it in an oversized manner we should stop fretting over those and focus on the big picture: which is to chose policies that provide the greater sustained benefit sooner. Finally, common sense morality can usually steer you in the right direction, but if it feels like it’s not, remember everything else in the book and you should be all set.

That’s all well and good, except that I kept imagining someone from Serbia — currently a second-world European kakistocracy — living by the standards of this book. Hilarity ensued: for things would be included in Wealth Plus that Cowen hadn’t foreseen (the ability to redraw borders, to name one), and common sense morality would include good doses of nepotism, chauvinism, and the desire to cheat the state (yes, yes, I know, #notallserbs).

So the first thing that’s keeping this book from being great is that it can’t be universally applied — it was written by an American for his fellow Americans who have lost their way — and doesn’t explore, or even mention, the implications of his vague concepts of Wealth Plus and common sense morality being different around the world.

The second is that shortly after admitting that economists don’t have crystal balls (the twelve-year-old me would have loved to put parentheses around “crystal”), he goes on to compare hypothetical policies based on their projected rates of growth well into the future. It may be my lack of an economic background speaking, but how can those two go together?

But do read the book. After my first pass I can say it’s good, if not great. For me as a doctor the idea of delaying gratification for long-term gains felt familiar. The oncologist in me would add that inflicting harm for a known long-term benefit is also reasonable and depending on the alternatives even preferred. Of course, it took centuries of wading in the dark before medicine got to the point where it could with any certainty predict the outcome of its interventions. Are social sciences there yet?

Written by Tyler Cowen, 2018

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Applied minds: how engineers think

I wanted to like this book more than I actually did. The title is seductive for those of us who work with people’s very unengineered fleshy bits: would it help if we added some engineering tools to our mental toolbox? Well, maybe it would, but this book couldn’t help me find them, being more of an essay on why I should think like an engineer rather than an instruction manual on how.

Apparently, you need a lot anecdotes anecdotes to explain the Why; stories zip by so fast they gave me whiplash. There are too many narratives and not enough thoughts: instead of just buttressing the main point or two, the anecdotes take center stage, sprinkled with outlines of different ideas that never become central.

For a book about engineering, I expected better construction.

Written by Guru Madhavan, 2016

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If on a winter’s night a traveler

The book is almost forty years old but it could have been written yesterday. It is short, smart, punchy, and very, very meta. It also makes me want to learn Italian, though I understand William Weaver is a good translator.

Written by Italo Calvino, 1981

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Ne, niko sa Stanforda nije pronašao lek protiv raka, i zašto uopšte čitate dnevne novine?

Znam da je u Srbiji nešto postala vest kada mi u par dana na WhatsApp dođe isto pitanje od tri različite osobe koje međusobno ne komuniciraju. Obično se ispostavi da je neko sa polu-znanjem engleskom i potpunim neznanjem medicine probao da prevede nešto što je neko sa za nijansu većim znanjem oba napisao na osnovu nečijeg saopštenju za štampu.

Zato, malo uputstvo za tumačenje vesti o medicinskim istraživanjima:

  • Ako istraživanje nije na ljudima već na životinjama ili ćelijskim linijama, prestanite da čitate;
  • Ako je istraživanje na ljudima ali se spominju reči kao “retrospektivno”, “intervju”, ili “ishrana”, prestanite da čitate;
  • Ako vest o istraživanju dolazi sa konferencije za novinare a ne iz objavljenog rada, prestanite da čitate;
  • Ako osoba koja piše vest nije potpisana imenom i prezimenom i nema iskustva u pisanju o medicini i nauci, prestanite da čitate;
  • Ako u vesti nema komentara od lekara ili naučnika iz Srbije koji stavlja nova saznanja u kontekst srpske medicine, prestanite da čitate.

(svaka od ovih stavki zavređuje zaseban tekst, prve dve i nekoliko, ali život je kratak)

Bez konkretnih cifara, imam osećaj da je broj tekstova koje vredi čitati u dnevnim novinama i nedeljnicima o lepoti i zdravlju nula, a u malo ozbiljnijim nedeljnim i mesečnim listovima 1-2 godišnje. Što je samo za nijansu manje od broja objavljenih radova koji uopšte zavređuju pažnju laika.

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The death and life of great American cities

Jane Jacobs loved Greenwich Village so much that she wrote a book about why that was and why more neighborhoods weren’t like it. She looked at other similar areas in Boston, Chicago, Philadelphia, etc. as well some failed ones, and gave a few guidelines on what was needed for safe, lively, and desirable city streets.

It has enough whimsical observations of city life to keep things interesting for its too-many—over 400—pages (e.g. on a city park’s homeless population: Almost imperceptibly, like the hand of a clock, the raggle-taggle reception creeps around the circular pool at the center of the square. And indeed, it is the hand of a clock, for it is following the sun, staying in the warmth. Or, comparing a safe-but-dirty city street to a desired but decidedly unsafe park: The sidewalks were dirty, they were too narrow for the demands put upon them, and they needed shade from the sun. But here was no scene of arson, mayhem or the flourishing of dangerous weapons. In the playground where the night-time murder had occurred, things were apparently back to normal too. Three small boys were setting fire under a wooden bench. Another was having his head beaten against the concrete. The custodian was absorbed in solemnly and slowly hauling down the American flag). It’s all quite lovely.

But ultimately, it is an exercise in confirmation bias that misses as many essential points as it reveals. What was arguably the most devastating influence on American cities — Robert Moses — is but a misguided elderly official who, and kudos to him, knows his way around public funds. City planners like big, disruptive projects because of their bad (deductive!) reasoning, not because they give politicians photogenic ribbon-cutting ceremonies.

If you want to know why American cities are the way they are, better read The Power Broker.

Written by Jane Jacobs, 1961

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The Last Jedi 👊

Extraordinary set pieces strung together by the thinnest of plots, based on an absurd, sitcom-worthy failure to communicate. A particular subplot should have been spun off as a buddy cop movie.

The Ray-Luke-Kylo triangle should have been a bigger part of the movie, but then many of the new characters, the ones that aren’t white and/or men, would have nothing to do. Such are the problems of building on an old and popular franchise: you can’t both stay true to the roots and change with the times.

It has cute animals and looks good in 3D though, so Dora (5.4) approves.

Directed by Rian Johnson, 2017

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