Richard Lehman reviews the latest research in the top medical journals

NEJM  9 Oct 2017  Vol 377

Breast cancer recurrence

We now know that there are about twenty different breast cancers, and each may have its own response pattern to treatment and risk of distant recurrence. Twenty years ago, we understood less: the main characteristics measured then were oestrogen receptor (ER) status and tumour diameter and nodal status (TN). More tumour information could no doubt be gathered retrospectively if someone did modern molecular analysis of all the histology samples from the 63,000 women in the 88 long-term follow-up studies which are meta-analyzed here. This is not going to happen. But let’s not worry: at least the New England Journal has at last published a systematic review—is this a first? We are left with confirmation that ER positive breast cancer behaves as a systemic disease, with a steady incremental risk of recurrence from the end of hormone therapy (98% tamoxifen in these studies) up to the 20-year mark. This is strongly associated with original TN status, varying between 10% and 41% with tumour size, grade, and lymph node involvement.

Mechanical v biological valves for replacement

Biologic/biological. It’s a US/UK thing. Same with physiologic/physiological. We Britons prefer to sound logical. Biologic(al) heart valves are made from a scaffold of animal tissue. They don’t come from a biochemistry lab, like biologic drugs for rheumatoid arthritis, or from a herb garden, like the biologicals we put in gin. Just thought you should know that. Here’s a great big observational study from California, comparing mortality outcomes, reoperations, and bleeding after mechanical v biologic replacement of the aortic and mitral valves. If you want to know the bottom line, you can take a look at the abstract. As nobody is trying to sell you anything, it is quite reliable. But is it sufficient? Isn’t it time that studies like this were turned directly into patient decision aids, by command of the NEJM editor?

JAMA  7 Nov 2017  Vol 318

Single-dose analgesics for acute limb pain

People came to two emergency departments run by the same institution in New York City with acute pain in an “extremity”—defined as anywhere distal to the shoulder or hip. This was classified by severity (moderate to severe) rather than by cause: about one in five had a fracture. On average, their pain scores diminished by over a third in the course of two hours, after they had been given one of four different analgesic combinations, all containing paracetamol. Paracetamol 1000mg with ibuprofen 400mg was as effective as paracetamol 300-325mg combined with any of three opioids: oxycodone, hydrocodone, or codeine. The bottom line message appears to be that an oral paracetamol/ibuprofen combination will relieve acute limb pain by 40% in most patients, and there seems little point in using opioids as first line treatment, though about 18% across groups needed “rescue treatment” i.e. extra pain relief in the first two hours. That’s fine as far as it goes. Unfortunately it only went for two hours, there was no measurement of adverse effects, and nothing to indicate whether it had an effect on long-term analgesic use. There is plenty more work to be done in this simple but important area.

Small lymphoma risk from IBD drugs

Treatment choices in inflammatory bowel disease are rarely easy, but at some stage most patients will receive a thiopurine (usually azathioprine) and/or an anti-TNF agent. Here’s a nice illustration of the importance of framing in risk communication. You’re a young patient with IBD and somebody tells you about a survey of nearly 200,000 IBD patients in France which measured the risk of lymphoma in people taking these drugs. “Taking azathioprine increases your lymphoma risk by 260% and if you take a TNF blocker too it might go up by over 600%.” Help: I am going to die. Or alternatively, “Taking azathioprine carries a very small risk of getting a type of cancer that is usually very treatable. It’s the difference between about a quarter of a per cent in 1000 years if you don’t take azathioprine and half a per cent in 1000 years if you do. If you need a combination treatment it goes up to about 1% in a thousand years.” Stares out of window: why is she telling me this?

JAMA Intern Med  Nov 2017

Does warfarin prevent cancer?

Now let’s look at this shared decision making/risk communication stuff from a different angle. Lots of decision aids have been produced to help people decide whether to take warfarin or a direct oral anticoagulant for say, stroke prevention in atrial fibrillation. This takes us to a central problem of therapeutics: it takes a long time to know the true effects of drugs. The DOACs are new drugs, divided into two broad classes, but there are within-class differences too, which are just beginning to emerge. And we don’t know the long-term risks and benefits of these drugs because they simply haven’t been around for long enough. Warfarin has been in medical use since 1954. But it has taken until now to discover that warfarin use is associated with a decrease in the total incidence of cancers, especially cancer of the lung, prostate, and breast. These data are robust and come from a whole-population Norwegian database. They could easily be checked using other whole-population databases. So all of a sudden a decision aid comparing warfarin with DOACs should perhaps have a box saying “Effect on cancer. Warfarin: reduces risk of several common cancers. DOACs: effect not known.”

Monty Python’s Meaning of Life and preventing diabetes

“Lady Presenter (John Cleese): Well, that’s the end of the film. Now, here’s the meaning of life…. Try to be nice to people, avoid eating fat, read a good book every now and then, get some walking in, and try and live together in peace and harmony with people of all creeds and nations.” The Meaning of Life (1983)

“Meaning:  For individuals at risk for diabetes, healthy lifestyle changes, weight loss, or use of insulin-sensitizing medications slow the progression to diabetes similarly; lifestyle modification strategies are better in the long term, although strategies to maintain their effects are needed.” Long-term Sustainability of Diabetes Prevention Approaches: A Systematic Review and Meta-analysis of Randomized Clinical Trials (2017).

Ann Intern Med 7 Nov 2017  Vol 167

How communicable are “non-communicable diseases”?

“The descriptor noncommunicable implies nontransmissibility, and the World Health Organization explicitly states that ‘chronic diseases are not passed from person to person.’ Current evidence indicates that this formulation is largely inaccurate in relation to current leading causes of death (LCDs). Two lines of evidence support this statement. First, a substantial proportion of the cancer-related chronic disease burden has been shown to have a transmissible, infectious cause; in addition, the pathogenesis of atherosclerotic vascular disease and type 2 diabetes also may have a microbial component, although communicability has not been established. Second, regardless of microbial causes, various behavioral risk factors, particularly smoking, diet, and exercise, are of central importance to all LCDs; these health-adverse behaviors are acquired primarily through social mechanisms and thus are communicable.”

Don’t have a shower today. You need to lie in the bath to do justice to a paragraph like this.

The Lancet 11 Nov 2017  Vol 390

The true heroes of medicine

If you are looking to do good in the world, where might you start? Perhaps in the Central African Republic (pop. 4.5m), which has the lowest level of human development and health in the world. Or maybe the Democratic Republic of the Congo, which has a much bigger population (78m) and ranks nearly as badly. In the 21st century, nobody should die from human African trypanosomiasis, caused by Trypanosoma brucei gambiense (g-HAT). The standard treatment is a combination therapy of oral nifurtimox and intravenous eflornithine that needs to be administered in a hospital setting by trained personnel. But there are few enough passable roads in these countries, let alone hospitals with the right drugs and patients who can afford them. By an amazing feat of courage, persistence, and logistics, Victor Kande Betu Ku Mesu and his colleagues managed to recruit nearly 400 people there with late-stage g-HAT and have shown that oral fexinidazole is effective and safe for the treatment of T b gambiense infection compared with nifurtimox eflornithine combination therapy. “Fexinidazole could be a key asset in the elimination of this fatal neglected disease.” Work of this kind is beyond admirable.

Tranexamic acid & the importance of time

As with thrombolytics, so with their opposites: time means lives. Tranexamic acid is a great drug for helping clots to stabilise and stop massive bleeding, and a meta-analysis of individual patient-level data from 40 138 bleeding patients shows that the sooner you give it, the better, whether for post-partum haemorrhage or trauma. It can reduce mortality by 70% given immediately, but “the survival benefit decreased by 10% for every 15 min of treatment delay until 3 hours, after which there was no benefit.” Just remember that: it could hardly be clearer.

The BMJ  11 Nov 2017  Vol 359

Three stages of shared decision making

Team talk; option talk; decision talk. Earlier in the year I was talking about this with Glyn Elwyn, who explains the rationale and testing of his modified three-talk model in a new research article. I think it’s a very useful starting point in conceptualising shared decision making, and in helping clinicians of all sorts (not just doctors) to adopt it in their practice. Personally I prefer the acronym ADD: alignment, discussion, decision. The most important stage is the first: align yourself with your patient’s aims and concerns. Never proceed without first establishing understanding and trust. Once you have done that, things that would otherwise be clunky and difficult become smooth and easy. You can be honest about choices, benefits, harms, uncertainty, and ignorance. This is a fruitful and privileged form of human exchange, and you may find it turns any burnout into its opposite: flourishing. That’s a hypothesis I would love to test with working clinicians and patients over the next few years.

Plant of the Week: Mahonia eurybracteata subsp. gangpinensis “Soft Caress”

For once I am writing about a plant I have never grown, or even seen. I used to collect mahonias a bit, though I have long grown out of space. This new one sounds like an absolute must, and as mahonias are tough plants, tolerant of almost any conditions, I’m sure we could squeeze it in somewhere.

Normally at this time of year I praise my favourite mahonia, good old M japonica which never fails to produce abundant long sprays of soft yellow flowers in November/December with the most heavenly scent of lily-of-the-valley. The trouble is that if you don’t wear spectacles, you can quite easily impale your eye on the tough, sharp-spined leaves as you lean to smell the blossom.

This mahonia, however, is called “Soft Caress” because it provides no clients for the Eye Clinic. It has soft elongated evergreen leaves which are, allegedly, pleasant to brush against. It has deep yellow honey-scented flowers in the autumn. Time to seek one out.