doctoring

I mean, I do? As do most of my friends who are homeowners. We are constantly asking each other for recommendations for people who can do X.

Hire a couple of disasters, and you will appreciate that a good relationship with a good contractor/tradesperson is worth an incredible amount of money (and time).

The not so big secret is that we can detect cancer early in a lot of people, but we also would detect a lot of not-cancer. We don't currently know the cost/benefit of that tradeoff for all these new types of screening, and therefore insurers and health systems are reluctant to pay the cost of the both screening and the subsequent workup. This is not just a financial consideration, though the financial part is a big part -- the workup for those that end up as not-cancer has non-negligible risks for the patients as well (I have had patients of mine suffer severe injury and even die from otherwise routine biopsies), and on top of that, some actual cancers may not really benefit from early discovery in the first place.

This is not to downplay the potential benefit of early cancer detection... which is huge. And in the US/UK anyway, there are ongoing large trials to try to figure some of this stuff out in the space of blood-based cancer screening, as part of the path to convincing regulatory bodies and eventual reimbursement for certain tests. As mentioned, you can currently at least get the Galleri test out of pocket (<$1k, not cheap, but not exorbitant either), as well as whole body MRIs (a bit more expensive, ~$2-5k).

I think this essay touches on but slightly conflates "younger" with "inexperienced". Younger people are inexperienced at more things in life, sure. But if you write essays about things that are new to the world (new technologies? events? societal changes?) then even older people may be inexperienced with it and could learn something, something that surprises the author and the reader.

Public service announcement: There are already blood tests for detecting pancreatic cancer and other cancers on the market, and more coming, depending on where you live. So get tested, if this is something you are worried about.

I believe the only commercially available one in the US is Grail's Galleri (https://www.galleri.com).

More info on this category of tests: https://www.cancer.org/cancer/screening/multi-cancer-early-d...

There are many tests in the pipeline -- although the technology is there, the regulatory and evidence process is slow. (Data relating to detecting cancer early, by its nature, takes a long time and a lot of people to prove out.)

I had the same question. From their FAQ (https://boomsupersonic.com/faq):

Will Overture use afterburners like Concorde?

No. Overture will fly without the use of afterburners, meeting the same strict regulatory noise levels as the latest subsonic airplanes. The airliner will be powered by the Symphony propulsion system. Symphony will be a medium-bypass turbofan engine designed and optimized for environmentally and economically sustainable supersonic flight.

I don't know for other countries, but for the United States, "medical students are no longer choosing it" is very very untrue, and it is trivial to look up as this information is public from the NRMP (the organization that runs the residency match).

Radiology remains one of the most competitive and in-demand specialties. In this year's match, only 4 out of ~1200 available radiology residency positions went unfilled. Last year was 0. Only a handful of other specialties have similar rates.

As comparison, 251 out of ~900 pediatric residency slots went unfilled this year. And 636 out of ~5000 family medicine residency slots went unfilled. (These are much higher than previous years.)

However, I do somewhat agree with the speaker's sentiment if for a different reason. Radiologist supply in the US is roughly stable (thanks to the US's strange stranglehold on residency slots), but demand is increasing: the number of scans ordered on a per patient continues to rise, as does the complexity of those scans. I've heard of hospital systems with backlogs that result in patients waiting months for, say, their cancer staging scan. One can hope we find some way to make things more efficient. Maybe AI can help.

Whole body MRI is fairly available in major metro areas, though not cheap and not very sensitive or specific.

The Galleri blood test screens for a range of cancers (sensitivity varies by cancer) and is ~$900, although you need a doctor to order it. You also may not technically be within the intended use population unless you have some risk factors (e.g. you are older than 50, or have family history of cancer).

Colonoscopy is a good idea, given the rising rates of colon cancer among younger adults.

"The tests... cover topics such as U.S. audit standards, professional ethics and independence..."

Ethics, you say?

"...involved hundreds of professionals, including partners and senior leaders such as the now former head of assurance..."

When the scale of these things is so large in a single firm, and only comes to light after 2(!) whistleblowers, it is hard to imagine that it is an isolated incident in the industry.

I love rice cookers!

Rice cookers (usually) make clever use of 1) alloys whose magnetism depends on temperature and 2) the fact that boiling water occurs at a fixed temperature. With a "trigger" temperature just above the boiling point of water, the rice cooker automatically turns off the heating element when all the water is gone (and thus the temperature starts to rise above boiling point).

More detail here: https://youtu.be/RSTNhvDGbYI

Very interesting overview of the technological / materials breakthroughs to enable miniaturization.

From a physician (specifically radiologist) perspective, I'm a big fan of handheld/point-of-care ultrasound and am excited about their potential at democratizing a very useful and low-cost/low-risk imaging technology. (I also own a Butterfly.)

That being said, the "cart-based" ultrasounds will likely always have a place in a hospital; the size of the ultrasound probes is not why the cart is big/expensive/useful. The cart is a big floating screen and also an image/record management system. You (or at least, a trained ultrasound technician) can manipulate ultrasound parameters and annotate images (critical for ultrasound interpretation) way way faster on the cart's set of wonky keys/dials/trackball than on a smartphone.

Also, with the rise of handheld/point-of-care ultrasound, we've noted with amusement in the radiology department the frequency with which patients get referred for additional imaging because the ED or primary doctor saw some pathology on their handheld ultrasound... and when we take a look it is just not there. I think this is probably more of a training issue, as ultrasound is truly quite challenging both to perform AND to interpret (and a major part of using an ultrasound probe is essentially real-time interpretation), which is even more challenging given the lower image quality and field-of-view of smaller probes.

They list it under their "legal documents" page: https://www.nabla.com/docs/business-associate-agreement

The article mentions: "...sequencing DNA from blood samples and tumour biopsies, to look for mutations that are found in the tumour but not in the blood."

This is pretty common for most cancer genotyping tests. (Sometimes they compare tumor with saliva or some other "benign" source, but the principle is the same.)

Wait, but we do have the tools...

We can (and do) cure so many cancers. Usually with surgery, +/- chemo/radiation. Sometimes just radiation.

It's hard to overstate how curable most cancers are at early stage -- for some it's well over 90% and approaching 100%.

The whole point of these screening tests is to try to find more cancers at more curable stages.

Your original comment stated:

They won't work for in situ tumors, almost by definition.

Which isn't true. The studies from multiple companies' tests demonstrate that they _can_ detect in situ tumors. Not always super duper well, and not always for every single cancer type, but still.

Whether this is a good idea / cost-effective is another question, and certainly a big deal as you point out.

This isn’t quite right — I think you’re thinking about circulating tumor cells (CTCs).

These tests on the other hand detect circulating tumor DNA (ctDNA), among other things. It is well known that tumors shed DNA and other material more than normal cells, even at early cancer stage. (Of course, later stage and more aggressive tumors are more indeed likely to shed more.) The detection limit for some of these tests is in the range of single digit copies of DNA fragment per mL of plasma.

Furthermore, the goal isn’t necessarily to detect every cancer as small as it could possibly be. Even if you don’t do a great job at finding all cancers at stage I, you may still save lives by detecting cancers at an earlier stage than they otherwise would have been found. Finding something at stage II instead of III or stage III instead of IV may well mean the difference of a shot for curative resection / radiation. (Whether these tests would be remotely cost-effective at attempting this at population scale... I leave as an exercise to the reader & healthcare system.)

Grail had a paper with some scant info on their test performance in multiple cancer types across all cancer stages. https://www.annalsofoncology.org/article/S0923-7534(21)02046...

Per the article, Grail’s test is already on the market at $949. Insurance does not cover this —- yet. (That is a big goal of many of these companies).

This is not cheap but not also not insane. Grail’s test screens for 50 different cancers (at a range of test performances, sure, but as the article mentions, many cancers currently have no screening mechanism). As comparison, the non-insured price of things like MRI and CT scans can run into the tens of thousands of dollars.

I was visiting family in NE Atlanta last fall. These spiders were everywhere -- coating houses, trees, power lines. And yet, they do not seem to come into homes. Even the exterminators they called said so.

Usually not!

PET scans are limited in resolution when you get down to the sub-5 mm or so range due to scanner technology and fundamental limits of the physics of positron/electron annihilation & photon emission.

A typical MRI (i.e. alas, not what this article is describing) can usually resolve something at that size and identify characteristics like diffusion restriction or contrast enhancement which can confirm metastasis.

Also, in the brain, PET scans (at least the most common, FDG, which is based on glucose) are extremely limited in utility because of the baseline high glucose metabolism of the brain, which makes it hard to distinguish from the metabolic activity of a tumor.

Rituximab is a monoclonal antibody which targets a B cell surface protein, CD20. Monoclonal antibodies are pretty cool, in that we've figured out how to make a thing that our bodies normally make, and engineer versions that target specific items we want. Antibodies binding to things can alter their function, disable them, and/or cause them to die. In the case of rituximab and CD20, through a variety of antibody-mediated mechanisms, the attached antibodies in effect causes the B cells to die off.

CAR-T cells, on the other hand, is essentially making a fairly small (but kind of insidious) modification to T cells in the lab. These T cells when put back in the body then do their normal T cell thing and proliferate and recruit more of the immune system, but to try to eliminate a target you've chosen for them. The most useful/successful target thus far has been CD19, another B cell surface protein.

Wow, I am so sorry. Thank you for sharing part of Melanie's story.

Your thought about the drugs maybe limiting the effect of the CAR-T is an interesting one and the subject of ongoing investigation. One common drug used for CAR-T related cytokine release syndrome, tocilizumab, does not appear to have negative effects on CAR-T proliferation or efficacy. However, it doesn't seem to do as much for neurotoxicity (which seems to be a separate mechanism from the cytokine system), and they often have to resort to steroids for that. Steroids do dampen T-cell activity, but to what degree that impacts CAR-T effectiveness is not clear. However, as you mention, sometimes you are left without much choice.

Choosing another target is a good idea! But, as you can imagine, we've been trying a lot of targets and they don't seem to work as well. One issue is that CD19 is the only known target that is a) expressed throughout the entirety of the B-cell lifespan, b) fairly preserved under immunological pressure, and c) is not expressed on other cells. Other targets do not maintain those characteristics and as such either won't catch all the tumor cells or will catch too many other cells. (CD21, for example, is also expressed on T-cells.)

That being said, there are studies ongoing for some of these targets in like "last last resort" capacity, as well as certain dual-target CAR-Ts looking at CD19 + another (CD22 or CD123, for example), to try to widen the net while tolerating a degree of on-target but non-tumor effects.

One could also imagine a way to more rapidly alter a patient's CAR-Ts such that you could quickly switch targets, or update them if their malignant CD19 was mutating. Currently the manufacture and production of CAR-T cells is very slow and expensive process, but I do have some friends working on improving that. Some are also working on the idea of a sort of "blank slate" CAR-T cell line which could be used in anybody, rather than being harvested from the particular patient in question.

re: CRS. It is still a significant risk, but our understanding has definitely dramatically improved over the past 10 years. We're getting better and better at anticipating, appropriately triaging, and providing necessary diagnostics & supportive care. That being said, severe outcomes and death do still occur. I don't know the numbers, to be honest.

re: the wimpy response. I am less well-versed in the immunological complexities but there are just so many steps which could contribute. Part of the CAR-T cell success requires them to continue to clonally expand after infusion into the body, and sometimes after infusion they just... don't. Or only a tiny subpopulation of them does. Why? We're not sure. Sometimes they fail to recruit the body's immune response. Why? Also not sure. Maybe it has to do with the health of the T-cells when they were harvested? Maybe something went wrong with the CAR engineering? Maybe with the host immune system?

Here's a decent overview of some mechanisms of relapse after CAR-T which might be a good jumping off point: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863137/

Yes. B-cells (normally) make antibodies, so these patients usually receive regular infusions of antibodies by IV (which come from blood donations) to keep their circulating antibody levels up.

There's a couple of reasons for why a person may relapse after CAR-T therapy, and much is still under investigation.

One large category is that the attack on the CD19 target has selected for B-cells which have a mutated CD19 or do not express CD19. This part kind of makes sense, and is somewhat understandable.

The other category is roughly that the CAR-T cells fucked up, and this is where things are a little murky. Sometimes the CAR-T cells kind of disappeared really quickly after infusion. Sometimes they're there but there's no significant immune response. Remember the therapy uses the patient's own T-cells which get "armed" outside the body and then re-infused. What if the patient's own T-cells are kind of uh, wimpy? Or their immune system overall is? (We know, for example, that T-cell immunity in general declines over age, which probably partly explains better results in younger patients than older).

Anyways, for various reasons, you can see why just "doing it again" may not work due to some issue with the targeting and the immune reaction.

Oh and also CAR-T therapy is not benign. You can get intense cytokine release syndrome where the (intended) activation of your immune system causes a ton of systemic effects (sometimes resulting in organ failure, seizures, death).

Nevertheless, sometimes they do try it again. I've had patients they've attempted CAR-T two or three times on. As you may guess, it was not effective.

CAR-T therapy is incredibly complex and incredibly cool.

One of the reasons CAR-T therapy has been so successful thus far with certain lymphomas and some leukemias is that there is a specific surface protein (CD19) which is expressed in all B-cells (the deranged lineage in the case of lymphoma) and is also not expressed by any other cells in the body. By engineering a patient's T-cells to target CD19, you create a highly sensitive and specific attack that recruits their own immune system to annihilate the entire B lineage population.

One problem we run into when trying this for other cancers (like, that don't come from B-cells) is that it's been really hard to find such a nicely specific surface protein, as well as an entire population of cells you can just annihilate and be survivable for the patient. Most surface proteins are expressed in varying degrees throughout various different organs in the body, so a CAR-T against it would cause a ton of off-target effects. In some early trials for certain cancers they encountered this with unfortunate side effects (including in some cases death). Nevertheless, there is lots and lots of research still ongoing in the field, which is super exciting, from trying out previously unknown targets, to figuring out how to better produce the T-cells, to enhancing the resultant immune response cascade, etc etc.

It’s worth noting that a test’s performance (i.e. sensitivity/specificity) is tunable. That is, Grail is making a decision of where to set its threshold for a positive result, in effect selecting where it wants to be on the ROC curve. For this version of this test they’ve chosen to keep the specificity very high, with the tradeoff being a low sensitivity. However, as this article alludes to, a low sensitivity can be okay if there isn’t any other screening modality — the alternative is essentially 0% sensitivity. (Like for, say, pancreatic cancer.) They can change the threshold to have a higher sensitivity but then will drop the specificity, and in settings of low prevalence (i.e. cancer in asymptomatic population) you quickly end up with a crazy false positive rate.

There are already ongoing trials with newer versions of the test (and many competitors not too far behind), but as you can imagine the challenge of demonstrating early detection gets harder the “earlier” you’re talking. (Longer study times, larger populations.)

In any case, highly recommend people read the linked study[1], particularly the confusion matrix which provides a quick overview of the test’s ability to identify the cancer’s source from just the blood. (That’s cool.)

Also, the Galleri test is already on the market in the US. (Via prescription by your MD.)

[1] https://www.sciencedirect.com/science/article/pii/S092375342...

Hey, radiologist here.

So, the question of "what next" after a positive result on one of these tests is still... open. The Grail test provides indication of likely tissue of origin, so a likely first step may be a targeted study (e.g. colonoscopy if it said a colonic source, MRI if it said pancreatic). There may be role for PET/CT as well to further stage and assess for metastases, perhaps after finding a lesion.

What to do if your blood test is positive but the workup is negative? Lots of discussion but nobody is quite sure.

As for a periodic full body MRI, I will say that currently uh, most of those are garbage. Unfortunately, for a full body MRI to be practical (that is, to not take hours and hours), you have to run very few sequences. (For example, a dedicated MRI of say, your brain or your liver alone could take about hour, each.) As a result, you greatly reduce your sensitivity for most pathologies, which kind of is counter to the point of the MRI to begin with.

Highly encourage reading the paper referred to (but not linked!) in the article:

https://www.annalsofoncology.org/article/S0923-7534(21)02046...

Some good breakdown of test performance by stage and cancer types.

Cancer radiologist here!

I don't know about "highly accurate", but certainly pretty fucking good. Because for most of those cancers for most populations, the asymptomatic detection rate is much, much lower. Like close to 0%.

There is no general population screening test for, say, pancreatic cancer or ovarian cancer etc.

They are trying.

For what its worth, faculty across multiple departments (including those radiologists) stepped up and declined their scheduled vaccine appointments until residents get vaccinated first.

It's a big place made up of mostly smart (and good) people. A lot of outrage is at the administration's poor planning, failure to respond quickly the problem, and subsequent excuse-making.

The residents who didn't get it: those working 80+ hrs/week in the emergency room, in the ICU, intubating patients, operating on patients, etc etc etc

Some people I know of who got it instead: Radiologists who primarily work from home. Administrative roles with relatively low (or no) patient interaction.

Not saying those people shouldn't get vaccinated -- just that if you were asked to come up with a priority list, it wouldn't be this.

Disclosure: am a physician at Stanford.