Richard Lehman’s journal review – 12 March 2012

Richard LehmanJAMA  7 Mar 2012  Vol 307
915   “Almost 2 and a half million people in the United States die every year, making death the most common health event in the United States” says Mary Tinetti in a Viewpoint piece called The Retreat from Advanced Care Planning. It’s a strange and somewhat disturbing choice of words, but then Mary is feeling somewhat disturbed. “In the months after the death panel uproar, family members of 2 patients accused me of being part of a government-backed plan to save money by not offering expensive care to frail older patients.” Instead, she wanted to talk about the kind of care that was humane and appropriate in the light of the common health event the patient was facing, i.e. death. So a moronic scare campaign dreamt up by Sarah Palin to undermine Obama’s Affordable Care Act has ended with patients and families being unable to discuss appropriate end-of-life care, and one of America’s foremost advocates for the elderly admitting that “These experiences left me feeling attacked and frankly reluctant to continue an activity that is the core of my responsibility as a physician.” God Bless America.

922   A couple of years ago, The Lancet published a case series by an eminent neurosurgeon from Queen Square reporting his superb results with surgery for epilepsy, with most of his patients cured after many years of fits (mostly temporal lobe) which were resistant to multiple medication. Here we have another bit of evidence that temporal lobe epilepsy surgery works – and again it’s not a proper, fully powered randomised controlled trial, but a study that was half-completed due to recruitment problems. These trials may not fit into the highest levels of the EBM hierarchy, but the figures here tell their own story: no complete seizure control in the non-surgical group (23), compared with 11 out of 15 seizure-free two years after surgery. No p-values needed.

NEJM  8 Mar 2012  Vol 366
883   The original title of the most famous text in biology was On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. The one thing that Charles Darwin could not explain in 1859 was how “favoured races” came to acquire their favourable characteristics. He could draw up a phylogenetic tree showing branching evolution, but until the coming of Mendelian genetics and the unravelling of the structure of DNA, nobody could explain exactly how this could operate through the processes of sexual reproduction. In fact it is much easier to observe at the level of asexual reproduction, in single-celled organisms like bacteria – or cancer cells. This ground-breaking British study traces the evolution of renal carcinomas using DNA analysis from the primary tumour site and various metastases. And what emerges is – you nearly guessed it – a phylogenetic tree showing branching evolution for each tumour line, as tumour DNA changes through furious cycles of unregulated division. This in turn means that any single tumour sample will not necessarily reflect the DNA of the cancer as a whole. The ideal of genomic analysis leading to personalized cancer cures gets a reality check when faced with this awesome demonstration of complex adaptive biology at work. Magic bullets will need to hit multiple targets at once: as these brilliant investigators drily remark, cancer heterogeneity “may present major challenges to personalized-medicine and biomarker development.”

893    And now for some more good British science supported by the MRC: The Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO) study. This was a multicentre, double-blind, placebo-controlled, clinical trial with a two-by-two factorial design. Most of us have long suspected that these drugs have no clinically meaningful effect on progression in Alzheimer’s disease and are largely a waste of money. Well, this trial proves us wrong. Even in patients as far gone as this, with Mini-Mental State scores between 5 and 13, both donepezil and memantine definitely slowed progression when continued, though combining the two had no additional effect. This study and the one before make it a great week for the UK Medical Research Council: glasses of best English sparkling wine should be raised throughout its premises.

925    Ever heard of the word abscopal? It sounds like some obscure ecclesiastical usage – a bishop performs abscopal ordinations outside his diocese, perhaps. Well, in oncology, it refers to the effect of a treatment at one site on metastases elsewhere. Specifically, we are told, “The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system.” Neat, and useful. This paper describes the case of a young woman with metastatic melanoma who received treatment with ipilimumab. This wasn’t achieving much until she had radiotherapy to a paraspinal mass. Thereupon all her other metastases started shrinking. Four years from the first discovery of metastatic disease, she remains stable on ipilimumab. Let us hope that abscopy proves to be a useful new direction in cancer treatment.

932    Which muscular organ is constantly active from birth to death, sustaining life without our commonly being aware of it? The QI hooter will go off if you answer the heart, although you will be technically correct, of course. But the structure I am referring to here is actually the diaphragm. There is never a week in these medical journals where heart disease is not mentioned, but I think this is the first article I have ever encountered on dysfunction of the diaphragm. We really do take our vital bellows for granted. The fact that we can is testimony to the diaphragm’s stolid efficiency in most conditions – except those rather rare and extreme ones described in this article, which I mainly mention for its value as a rarity.

(Someone should write an Ode to the Diaphragm, beginning,
Lo, thus I breathe!
Therefore I am!
Let us extol the Diaphragm!
That with its soft unnoticed thrusts
Sustains our life by vital gusts.)

Lancet  10 Mar 2012  Vol 379
895   “The Lancet, you may have noticed, is a seriously weird journal. One of the things it likes to do is publish the results of cutting-edge human experiments before they have any clear outcomes” I wrote here two weeks ago. This hasn’t changed in a fortnight, and in fact it hasn’t changed in over a decade. During this time there have been lots of small trials of stem cells for repairing myocardium: these were novel and exciting to begin with, but you might be forgiven for wanting some evidence of actual benefit by now. Here in the latest phase 1 trial, CADUCEUS, the stem cells were cardiosphere-derived, i.e. grown from the patients’ own cardiomyocytes obtained by endocardial muscle biopsy. Cultured autologous precursor cells were introduced by coronary artery infusion, and at six months there was MRI evidence of scar repair and new myocardium but no change in functional indices at all. There will now be a phase 2 trial. Can’t wait. You may want to read more about what hasn’t yet happened in this field in the review article, towards regenerative therapy for cardiac disease.

905    In the days when I was still a proper doctor with a consulting room of my own, I used to shock and confuse visiting health professionals by keeping a mercury sphygmomanometer with an adult cuff that covered 80% of the upper arm. That way I could at least believe my own blood pressure readings. I even tried to keep abreast of the hypertension literature for a while, since it seemed best to know something about the commonest reason for treating healthy people in primary care. And I even uncovered the odd case of primary hyperaldosteronism. But I very rarely measured the BP in both arms, except in one memorable lady with a cold hand and a loud subclavian murmur, who provided my one and only diagnosis of subclavian stenosis. Here is a frustrating systematic review of the difference in BP between arms and vascular disease and mortality – frustrating because it doesn’t place its findings in any useful context. In particular there is a digression about the ankle/brachial pressure index without a direct comparison with the arm/arm BP index, but without clarifying which is more useful in which clinical situations. The authors are willing to commit no further than some mights and coulds: “A difference in SBP of 10 mm Hg or more, or of 15 mm Hg or more, between arms might help to identify patients who need further vascular assessment. A difference of 15 mm Hg or more could be a useful indicator of risk of vascular disease and death.”

BMJ  10 Mar 2012  Vol 344
The latest and best meta-analysis of randomised trials of self monitoring of blood glucose in people with non-insulin treated type 2 diabetes uses individual patient data to show once again that use of this expensive technology does not lead to any clinically meaningful improvement in glycaemic control. It’s high time that guidelines such as NICE reflected this. We encouraged this practice once, in the belief that it would help patients manage their condition better. Then it became a lucrative scam for the test strip manufacturers who could change their systems every few years to ratchet up costs which are borne by the NHS. Now it’s time for a reality check, and for some serious questions about futile spending to be addressed.

I’m not a great fan of modelling and simulation and cost-effectiveness studies, though these seem very popular with the BMJ. I like things that I can understand and interrogate. Still, I was rather intrigued by the notion of a Dutch microsimulation model. Does it contain little dykes and windmills and adjust for cannabis use? Prosaically, it is merely based on Dutch cervical screening data, and it reaches a conclusion that I have been wanting to hear from some time – most European countries should consider switching from primary cytology to HPV screening for cervical cancer. But still, Nullius in Verba – the Royal Society motto which roughly means “don’t take their word for it.” Anything which requires specialist software, Dutch or otherwise, can only be taken on trust.

In 1991, my practice took on a brilliant new partner who was a paediatrician with a special interest in asthma. I can remember saying to him at interview, “Oh good, we need you to sort out the mess which is childhood asthma.” In those days, not only did every child who had ever wheezed get the asthma label for life, but also every child who coughed for more than a month, especially at night. Nowadays we distinguish – as we easily could then, if only we had been given official permission to – between pre-school wheezing, post-infective wheezing, atopic asthma, post-infective cough and chronic cough in children. Here at last is a practical review of the last topic which plainly states that “Isolated cough without wheeze or breathlessness is rarely caused by asthma”. Some time ago, our practice took part in a study by Anthony Harnden which showed that up to 25% of persistent cough in children and adults is associated with evidence of recent pertussis infection, but most people still seem to be unaware of this. There is nothing to be done but wait it out, anyway. For other diagnostic possibilities, and sensible management advice, keep this article.

Ann Intern Med  6 Mar 2012  Vol 156
329    A simple and outstandingly useful Dutch RCT demonstrates clearly that early treatment of rheumatoid arthritis with methotrexate and prednisone 10mg daily is superior to methotrexate alone. The primary end-point was erosive joint damage at 2 years. But combination treatment was also superior for minimizing the need for DMARD and biological drugs, and caused fewer adverse effects.

340    Lisa Schwartz and Steve Woloshin have tirelessly striven for over a decade to help people understand how to interpret basic medical numbers and concepts. Some of their effort has been directed at patients, some at the general public, some specifically at journalists, and some at doctors. In this classic study they and two colleagues look at how well American primary care doctors understand cancer screening statistics. The news is worse than you could have believed. “When presented with irrelevant evidence, 69% of physicians recommended the test, compared with 23% when presented with relevant evidence (P < 0.001). When asked general knowledge questions about screening statistics, many physicians did not distinguish between irrelevant and relevant screening evidence; 76% versus 81%, respectively, stated that each of these statistics proves that screening saves lives (P = 0.39).” Aargh.

360   The previous study is not by any means the only one to show that doctors can be very poor at handling numerical data; there have been lots of studies in patients too, and some in surrogate decision makers. Here is a mixed-methods (hurray!) study of how relatives and decision-making carers of people incapacitated by serious disease interpret prognostic information, whether given as numbers or words. Such discussions usually take place in the context of continuing life-supporting treatment, so this could hardly be less trivial. And the investigators find that misunderstanding is rife – and tends to be in one direction only, so that it is not simply misunderstanding but cognitive bias towards optimistic interpretation.

Plant of the Week: Helleborus x ericsmithii

As the growing season begins to unfold its delights, the plants I most look forward to are the hellebores. Alas, I have found none so far in New Haven, perhaps because the soil is lime-free and unfavourable to the whole genus. Or perhaps it has been too cold so far. Back in England, our garden must be awash with self-sown oriental hellebores with their perfect flowers of white, black, pink and yellow, spotted or otherwise – or intriguing dull green, as in the amusing cultivar “Old Ugly”.

We also miss the chance to buy new hellebores, which must be done while they are in flower, and from a specialist nursery with a decent choice. I would like at least to see the one named for the greatest of hellebore fanciers gone by, Eric Smith. It has leaves of veined pewter with long flower-stems bearing white flowers with a hint of pink. I think if I saw it I would buy it. I might have already. That’s the nice thing about old age, as Ronald Reagan remarked.