Richard Lehman’s journal review—9 November 2015

richard_lehmanNEJM  5 Nov 2015  Vol 373

Now for the good news

1824   In the middle of the joy and uncertainty of pregnancy, you are told you have cancer. It happens to a few women every week across Europe. Thanks to a collaboration between national referral centres in Belgium, the Netherlands, Italy, and the Czech Republic we can find out what happens to children born to mothers who were treated for cancer while pregnant. Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. I love reading this kind of study from bodies like the International Network on Cancer, Infertility, and Pregnancy: medicine as a collaborative endeavour for people facing distress. This will come as immensely welcome news for women in one of the worst situations that life could throw at them. Let’s hope longer term data are equally reassuring.

Tiny trial weaves a threadbare mantle

1835   Nobody knows how to treat mantle cell lymphoma, according to the introduction of this paper. I certainly don’t. For me as for most readers, this trial just stands as an example of the kind of thing that passes for evidence in the world of uncommon cancers. And on both sides of the Atlantic, standards are set to worsen. Take 38 people with mantle cell lymphoma of varying grades. Give them all the same regimen of rituximab and lenalidomide. Report the response rate before median progression-free survival data were available. That’s it folks. Now everybody with mantle cell lymphoma will want to get rituximab and lenalidomide at a cost of about £10K per month at the dosages used in this tiny unblinded uncontrolled trial.

Tapeworm eats brain shock horror

1845   You’ve already read this one. If you haven’t, you need to right away or you are not cool. Journals need to print stuff like this from time to time, to make headlines. The NEJM’s excuse is that “Invasion of human tissue by abnormal, proliferating, genetically altered tapeworm cells is a novel disease mechanism that links infection and cancer.” Yeah, right.  That should be “infestation” not “infection.” See me after school assembly.

Oh suPAR – a new marker for “chronic kidney disease”

OL   You thought you were healthy until someone measured your imaginary glomerular filtration rate (eGFR). Then you were told you had grade 2 chronic kidney disease. You obediently turned up for a repeat creatinine measurement after a year. This time they decided to measure your plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) as well, because they had read this study in the NEJM. “In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m2, the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile.” “Progression to CKD” was defined as moving to an eGFR below 60. There was no attempt to link suPAR with any patient meaningful endpoint. So my questions would be: in what way could this test provide information that makes any difference to anyone’s outlook or management? Is it even ethical to do tests which leave doctors unable to explain their meaning to individuals?

JAMA  3 Nov 2015  Vol 314

Disingenuous denial

1791 “Confluence, Not Conflict of Interest” now appears in print, and leads me to break my rule and comment on this article a second time, because I think it marks a low point for JAMA. It aligns the journal with the disingenuous deniers who pretend that conflicts of interest don’t arise when authors and investigators write about work that they have a vested interest in promoting. It joins together JAMA with the NEJM which took a similar stance in a series of opinion papers earlier this year. This is a sort of Republican Tea Party of the soul, where you know you are saying something false and daring people to contradict you, knowing that their very engagement is a form of legitimation. And besides, you have power over them and they don’t over you. Blake called this place Ulro, and it leads to nothing but harm and barrenness—for those involved as well as for everyone else. But it is perfectly possible to get out of Ulro and build a better world.

Prescribing in the USA

1818   On the face of it, total prescribing hasn’t gone up that much in America over the last decade or so. In a survey comparing the year 1999-2000 with 2011-12, 8% more Americans reported taking at least one prescription drug, bringing the total to 59%. But the prevalence of polypharmacy (use of ≥5 prescription drugs) increased from an estimated 8.2% in 1999-2000 to 15% in 2011-2012—in other words, it’s probably now double what it was 15 years ago. You can look up the rest for yourselves, as this article is open access. How do you think we should go about reversing this trend? For example, do you think it would help if we encourage “confluence” with people who have a vested interest in selling more drugs?

Sucking away the stroke clot

1832   Stroke medicine is in a funny place at the moment. On the one hand there is hot debate about the dependability of the trials which led to thrombolysis using alteplase becoming a standard treatment, while on the other there is a rush to promote the addition of endovascular clot removal to improve the outcome of thrombolysis. Here’s a meta-analysis which tries to determine the current state of knowledge about endovascular thrombectomy. “Among patients with acute ischemic stroke, endovascular therapy with mechanical thrombectomy vs standard medical care with tPA was associated with improved functional outcomes and higher rates of angiographic revascularization, but no significant difference in symptomatic intracranial hemorrhage or all-cause mortality at 90 days.”

Elephant in the cancer room

1850   For once, the elephant in the cancer room is not the unaffordable cost of cancer drugs. It is an actual elephant. Look up and behold this most adorable of pachyderms: its chance of dying of cancer is less than 5%. Ours is 11-25%. The authors look at various genomic reasons and end up with the usual steaming heap of … possibilities.

Lancet  7 Nov 2015  Vol 386

Prophylactic antibiotics may harm severe stroke patients

1836   People who have dysphagia following a stroke are at high risk of inhalation pneumonia, which can lead to death. This trial, which was strung over four years and 48 stroke units, randomised patients in this category to receive prophylactic antibiotics (usually amoxicillin with clarithromycin) for seven days. The outcomes were really counter-intuitive. The active group had poorer outcomes generally. They showed a (statistically non-significant) lower incidence of Clostridium difficile and MRSA colonisation. They had the same rate of pneumonia but fewer urinary tract infections. But there was a just significant higher 90-day mortality rate in those given antibiotics and they tended to stay in hospital longer. It’s all very odd, and I wonder if clarithromycin interactions and cardiac effects could be playing a part in this.

FAME & follow-up

1853    When the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study first appeared, I seem to remember greeting it with the well-known quote from Milton’s Lycidas:

Fame is the spur that the clear spirit doth raise

(That last infirmity of Noble mind)

To scorn delights, and live laborious dayes;

(Poems of Mr John Milton, 1645)

I suspect I’m not alone in finding few things more laborious and less delightful than working through interventional cardiology trials. For those who are still reading, “Fractional flow reserve (FFR) is defined as the ratio of maximum blood flow in a stenotic coronary artery to maximum blood flow if the same artery were completely normal. An FFR of 0·80 or less, as measured with the use of a coronary pressure wire during invasive coronary angiography, indicates the potential of a specific stenosis to induce myocardial ischaemia with an accuracy of greater than 90%.” So it seems worth measuring. And indeed the original two-year follow-up showed a benefit compared with standard angiography when used as a guide for percutaneous intervention in people with multivessel disease. Following the participants up for another five years shows little further benefit over that period. I cannot tell you how this fits into the general perspective of interventional cardiology in 2015. These waters are deep and easy to drown in, as Lycidas drowned off the coast of Wales:

Ay me! Whilst thee the shores, and sounding Seas

Wash far away, where ere thy bones are hurld,

Whether beyond the stormy Hebrides,

Where thou perhaps under the whelming tide

Visit’st the bottom of the monstrous world…

BMJ  7 Nov 2015  Vol 351

Some Like It Hotter

This study of data from Florida has caused alarm and despondency in the circles I move in. Our slogans are “Less is More” and “Choosing Wisely,” but here is seeming proof that if you don’t overinvestigate and overtreat, you’re more likely to get sued. But wait a minute. These are data from hospital patients in Florida. They are skewed by obstetric figures in a culture where if you don’t do a caesarean section you are fair legal game for a malpractice suit if anything bad happens. And it’s the same for everything in Florida, to go by the Dartmouth Atlas of Variation. Once you get there, unless you’re Marilyn Monroe in Some Like It Hot, you’ll get more diagnoses than you ever heard of. More of your own money will be spent on persuading you that you are ill than almost anywhere else on earth. And once you’ve parted with most of your money on the pretext that you need treatment and tests on an almost daily basis, you will naturally visit a lawyer as soon as something happens to you for which you haven’t had a treatment or test. This study just shows what happens when a health system has gone utterly utterly mad.

Nonsteroidal Anti-Improvement Drugs

I’ve just been up to Middlesbrough to talk to a group of GPs and hospital doctors on themes of overdiagnosis and overtreatment. It was a genuinely humbling experience. This terrific group of doctors were clearly doing their utmost to deliver patient-centred medicine when every constraint is against them: mismatched evidence, time pressures, and distorted incentives of every kind. Most of the time I felt a prat talking about how to do things they were already doing better than I did when I was actually seeing patients under better conditions. I did however speculate that some of the harms that we see in elderly patients are due to non-steroidal anti-inflammatory drug interactions. I brought up this issue recently in my spironolactone blog too. Here comes real evidence in the form of a survey of variations in prescribing safety in UK general practice, based on massive data from the Clinical Practice Research Datalink. NSAIDs feature in half the instances of dangerous co-prescribing. Note the “prescribing” word: lots of NSAIDs are bought over the counter too. If you are a GP, click on the link and print out this paper to discuss at your next practice meeting. You are already doing a great job in impossible circumstances. Here is a simple prescribing audit tool to do it even better.

More interventional cardiology: run!

Treatment strategies for coronary in-stent restenosis: systematic review and hierarchical Bayesian network meta-analysis of 24 randomised trials and 4880 patients.” Bye.

Fungus of the Week: Tuber melanosporum

The black truffle of the Périgord is famously amongst the most expensive fungi in the world. I hadn’t tasted one until I was about 55, but thanks to a recent discovery, I think I’ll be enjoying the taste of black truffle every week from now on.

Despite their firm, woody appearance, truffles don’t keep for very long. That is one reason for the huge prices paid for fresh truffles. And although they have been declining in the Dordogne, they remain relatively abundant in parts of Italy, especially the Abruzzo. A friend who lived there for some months could get fresh black truffle shaved on to pasta or risotto at any local restaurant as a matter of routine.

The life changing discovery I made just over a week ago was a Sardinian cheese called moliterno al tartufo, sold on a stall at Banbury’s vestigial Thursday market. I’ve had various cheeses with a bit of truffle in them before, but this one is sensational. It’s made with unpasteurized ewe’s milk from the wild hills of the most enigmatic island in the Mediterranean, interleaved with veins of black truffle. The truffles must come from the Italian mainland, since the first find of black truffles in Sardinia merited a learned article in 2009. Or maybe the hounds and the pigs have been out in force there and discovered a whole pile more since then.

This cheese will fill your whole fridge, nay your house, with the scent of truffle. This is quite a good thing, but you can do better. Place the cheese in an airtight container with as many fresh eggs as possible. Eat these eggs after a couple of days, boiled, poached, or scrambled. They will be the eggiest eggs you have ever eaten, and carry the subtlest hint of truffle.

As for the cheese itself, shave it on to buttered pasta, risotto, or even just buttered toast. But don’t try melting it: that doesn’t work. Try it with tomato based salads, but be sure to honour it with the best tomatoes you can find. A £10 piece of this cheese will pay for itself, because you’ll want to eat the cheapest foods with amazing new pleasure.