Richard Lehman’s journal review—12 June 2017

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  8 June 2017  Vol 376
Dissecting nodes in melanoma
Read carefully now, because what I am about to tell you may seem odd. Say you are diagnosed with malignant melanoma, and the sentinel node is positive for cancer. What’s your first thought? Perhaps “Help, I’m going to die. Take my other nodes out while I draw up my will.” But all that is completely wrong. In this randomised trial, disease specific survival in such patients at three years was 86% if they underwent immediate lymph node dissection and 86% if they did not. Those who had all their nodes removed had a 24% rate of lymphoedema compared with 6% in the observation group. For further enlightenment, read the editorial, which begins: “Because of an incomplete understanding of regional lymph nodes, they have been characterized either as active filters or barriers to the distant spread of disease or as passive indicators of the risk of distant spread. The truth almost certainly resides in a hybrid model that embraces aspects of both theories. This lack of understanding has frequently led to a ‘more is better’ philosophy in the surgical management of regional lymph nodes. Yet in melanoma, as in so many other cancers, the elective removal of clinically negative nodes has rarely, if ever, been shown to increase disease specific survival.”

Lithium in pregnancy and cardiac malformations
Lithium taken in pregnancy has been associated with cardiac abnormalities in the offspring, especially right ventricular outflow tract obstruction defects. In a massive study of over a million American births covered by Medicaid, the rate of these was 0.60% among lithium exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06). So there almost certainly is an added risk, but notice how the 95% confidence interval includes unity.

Data sharing and journal editors: sauter pour mieux reculer
It seems an age ago, but it was just January last year that the editors of the leading medical journals signed up to a bold declaration of intent to insist that authors should be prepared to share their full datasets with others. NEJM’s editor then began to show intense signs of unease about the statement he had just lent his signature to. This hasn’t really abated since, as shown by two contrasting perspective pieces this week. One is by a NEJM writer and quotes mainly from people who don’t accept the need to share data, except among themselves. The other is from a patient who can’t believe that researchers don’t welcome the fullest possible use of information provided by patients who volunteer to undergo the risk of testing new treatments.

Meanwhile, the editors who took a bold leap of faith last year are now moving back a step or two, ostensibly because nobody has yet sufficiently solved the practical issues of sharing trial datasets. For heaven’s sake, I know I’m biased as a member of YODA and AllTrials, but it’s long past time that medicine got its act together on this.

Small breast cancers and overdiagnosis
Are Small Breast Cancers Good because They Are Small or Small because They Are Good?” Did this paper get into NEJM because it has such a good title, or was the paper so good that the NEJM came up with the cool title? Or did the NEJM come up with the cool title and then commission the special article? You can see the problem. It’s the same with cancers. We know that mammographic screening detects mostly lesions that would never grow and spread, but we also know that breast cancer can be considered as a systemic disease from the start. What we don’t know is how to handle this knowledge, and all the while it’s becoming clear that there are at least a dozen kinds of breast cancer (or is it a hundred?) with different biological and prognostic features. This paper gives a few clues from present knowledge of the relationship between cancer genotypes and size. But believe me, this is an area where the data change week by week and interpretation struggles to keep pace.

SLGT2 inhibitors
I’m delighted that drugs have been discovered that actually improve cardiovascular outcomes in type 2 diabetes. Inhibitors of sodium–glucose cotransporter 2 (SGLT2) observationally do this as a class effect, and definitely did so (unexpectedly) in a major randomised trial of empagliflozin. But from a letter in this week’s NEJM it seems that a certain amount of caution is needed. Compared with another class of drugs used as second line treatment, the dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors are associated with twice the risk of diabetic ketoacidosis. The detail of this needs more than a letter can contain, but it’s clear that these promising drugs need a watchful eye.

JAMA 6 June 2017  Vol 317
Home treatment following severe COPD episodes
These 116 British patients with chronic obstructive pulmonary disease were sick people. They had persistent hypercapnia, and of the 59 randomised to home oxygen alone, 19 were dead within a year. The other 57 received non-invasive ventilation in addition to oxygen, and of those 16 died. The main difference was in time to hospital readmission: 1.4 months versus 4.3 months.

Desirable weight in pregnancy
This survey of 1.3 million American pregnancies gives me the opportunity to tell you belatedly that the US Institute of Medicine (IOM) is now called the National Academy of Medicine (NAM), and has been for over two years. When it was still the IOM, the luminaries who sat there decided on the desirable range of weight gain for women during pregnancy. Roughly speaking, they seem to have got it right. Women who put on too much weight (47% of the sample) have bigger babies and more caesarean sections, while women who put on too little tend to have smaller babies and a higher risk of premature birth.

JAMA Intern Med  June 2017
Salt in American food
I don’t really care how much sodium there is in food, provided it doesn’t taste too salty. American food always tastes too salty. This article tells us that packaged American food is less salty now than in 2000, which still can’t possibly bring American packaged food to the level of edible. For that they would need to tackle the real problem both for taste and health: corn syrup. And most of the other stuff in American packaged food.

Persistent pain and cognitive decline
Here’s a sad study of 10 067 Americans aged between 67 and 78, of whom 11% suffered from persistent pain. These people showed lower baseline score for activity and higher scores for depression at baseline. And after 10 years, they also showed a higher rate of dementia.

Glucose strips in orally treated T2DM: America catches up
To celebrate the tenth anniversary of Andrew Farmer’s landmark BMJ paper showing that self-monitoring of blood glucose is a waste of time for Britons with type 2 diabetes who are not on insulin, JAMA IM publishes this North Carolina study, which shows that the same is true for Americans.

The Lancet  10 June 2017  Vol 389
“Tildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis.” For “evolving treatment strategy” please read “drug that Merck is trying to sell in a highly competitive market for new mabs.” In two phase 3 trials, funded by Merck, it performs well against placebo. Against etanercept, the difference is not great: it’s expressed as a difference of percentages achieving changes in psoriasis area and severity index (PASI) points and the detail is complicated and attached to a series of clinically meaningless P-values. The big question is how much value this mab adds to the treatments that are already standard. I have absolutely no idea.

From one of the commonest skin conditions to one of the rarest: cutaneous CD30-positive-cell lymphoma. And for every disease there is now a mab that somebody wants to sell: this one rejoices in the name of brentuximab vedotin, made and trialled by a subsidiary of Takeda Pharmaceuticals. But enough of this; I fear I am losing my audience. The Lancet may have seen fit to publish this trial, but for most of us, brentuximab vedótin is hardly worth the nótin’.

The BMJ 10 June 2017  Vol 357
Reporting of RCTs: from poor to middling
At a rough estimate, I have read the abstracts of over 2000 Cochrane reviews in the past three years or so. It’s quite a reality check if you want to believe in evidence based medicine. The authors of this study went through about the same number of Cochrane full reviews published between 2011 and 2014, and found that they took their data from 20 920 randomised controlled trials. Then they analysed the reporting of all these trials. Yes, they looked at 20 920 RCTs and they have lived to tell the tale. Over this relatively brief time span, they were able to detect an overall improvement in the reporting of summary data from RCTs, which offers a glimmer of hope. But for many, especially if reported in low impact factor journals, the standard remains dire.

Hammering the hippocampus
If this MRI study of the effects of alcohol on the brain is to be believed, my scan would show complete absence of the right hippocampus. Which is fine by me: we live to use up our organs, and I am old. “While those consuming over 30 units a week were at the highest risk compared with abstainers (odds ratio 5.8), even those drinking moderately (14-21 units/week) had three times the odds of right sided hippocampal atrophy (3.4). There was no protective effect of light drinking (1-<7 units/week) over abstinence.” Ah well.

Poem of the Week: Lines on the Life & Work of S T Coleridge (1772-1834)

Coleridge needed cuddles.
He seldom got them from his mother,
Which led to all his muddles
Seeking them from another.

He married a woman called Sara
Then found he couldn’t bear her,
And sought another of similar name
But found she wouldn’t do the same;
Though once on a sofa with her sister
They petted him: O, how he missed her!
He fled, unable to cope with them
And took to drinking opium
Mixed with a pint or two of brandy
To stop him ever feeling randy.
Brief verses can hardly relate
How often he failed to mate:
It is a tale that needs two tomes
Fortunately written by Richard Holmes.

And so it went on, and on – and on a bit more, like the Ancient Mariner,
Until the reader hits a barrier:
Why o why was he always fuddled
When all he needed was to get cuddled?
Coleridge was the greatest man that England got to make
Except Shakespeare, Turner, and William Blake.

  • George

    Why do the DKA cases caused by SGLT2 inhibitors have a low rate of hospitalisation?
    Because in most cases they are simple non-diabetic ketoacidosis – a slightly elevated ketone level has bumped against the loss of electrolytes caused by the SGLT2i’s side effect of natriuremia, uncomfortably widening the ion gap.
    (But maybe not even that in some cases – it seems likely that many of these reports could be based on ketone readings alone)
    This is only being diagnosed as diabetic ketoacidosis because the patients have been diagnosed with diabetes, and they now have ketoacidosis (or perhaps just hyperketonaemia).
    Why does the SGLT2i cause this?
    It’s inhibiting an insulin-activated renal transporter for the re-uptake of glucose and sodium.
    Glucose runs out of the body, and if this happens too much and the level drops too low the liver must increase gluconeogenesis to replace it. This removes oxaloacetate from the Krebs cycle. If enough oxaloacetate is removed, the acetyl-CoA from fatty acid oxidation can’t be fully metabolised and will be exported as ketone bodies instead.
    It would seem to be simpler and safer to manage the glucose level by eating less of it, as there don’t seem to be any case reports of ketoacidosis related to dietary ketosis in people with diabetes restricting carbohydrates.

  • Justin Coleman

    Delightful reading, as always, thanks Richard.

  • Mark Paulsen

    Next time you are in America give me a call and I will buy you a few units.

  • Wes Lisker

    Here, here. Eating less of it. Somehow this is pertinent to Leyman’s taste assessment of American food and its not so tasty contents.