Richard Lehman’s journal review – 13 June 2011

Richard LehmanJAMA  8 June 2011  Vol 305
2295    Ovarian cancer almost always presents too late for a cure, so screening asymptomatic women must offer our best chance of reducing its high mortality. In this ground breaking study, 78 216 women were randomised to usual care or to have CA-125 measurements every year for 6 years and transvaginal ultrasound every year for 4 years. Here are the follow-up figures 10-13 years later. In the screened group, the detection rate for ovarian cancer (212 cases) was higher, but failed to reach statistical significance. There were 3285 false positive results – 15 for every true positive – and over one thousand women underwent unnecessary surgery, of whom 163 experienced at least one serious complication. And the effect on ovarian cancer mortality? A tiny bit higher in the screened group.

2312    The conquest of many childhood cancers is one of the success stories of postwar medicine, showing that the fine-tuning of highly toxic treatment regimens can sometimes lead to dramatic rates of cure. But always at a price. The British Childhood Cancer Study looks at the late cost in terms of new cancers after 25 years. There is a fourfold increase of risk, concentrated on gastrointestinal and genitourinary tumours, most of which seems to be attributable to abdominal irradiation for lymphoma or Wilms tumours. The authors argue that adults who have survived such treatment should have regular colonoscopy because of their increased risk of colorectal cancer.

2320    You’ll have gathered by now that this issue of JAMA is devoted to cancer. Now I am writing from the USA, where it is a known fact that every British GP has sat on a Death Panel and gleefully withheld life prolonging treatment to the pleading, wasted cancer patients who queue up at the barred gates of his socialist health facility. That aside, there’s some pretty good debate over here about the unaffordability of many new cancer drugs, such as sipuleucel for advanced prostate cancer (see p.2347). One way to overcome this might be to try out orphan drugs – compounds off patent, with known pharmacological actions but no clear uses – in trials on cancer patients. Alas, this study shows that the incentives offered to pharmaceutical companies to do this have resulted in a rash of badly conducted, nonrandomised, often open-label, trials: exactly the sort we need least in life-threatening disease.

2327   Now there’s no clearer sign that you’re on to something in medicine than when people who ought to be dead remain alive. That’s the exciting aspect of this trial of imatinib in advanced malignant melanoma. OK, this was a small open-label study (n=28) of a highly selected subgroup with mutations of the tyrosine kinase receptor KIT. Twenty-four of them are now dead. But two are showing long-term control and two are in complete remission. And it seems that their response fits the genomics of their tumours: not a great step forward, so far – but a definite step.

NEJM  9 June 2011  Vol 364
2187   Poorly old people with aortic stenosis can decompensate and die if you don’t do something at the right time, or else they can die on the table if you do. The middle way between fatal inactivity and fatal open valve replacement is transcatheter valve replacement, which has been shown to be effective for those definitely too unwell to have a thoracotomy. This trial attempts to assess the risks and benefits of those half way to being too poorly – and ends up with a complex balance of benefits and risks. An open op may kill you sooner if you’re unlucky, but survival at one year is the same with the two procedures; on the other hand, you are slightly more likely to get a stroke or a peripheral artery complication with the closed procedure. I don’t envy those who have to make these decisions – patients as well as doctors.

2208   “The 6-month rate of expulsion of an IUD after immediate insertion was higher than but not inferior to that after delayed insertion.” Now the editors of this august journal deserve my gratitude for publishing a letter with my name under it, on the very day I landed in New England (it’s really John Yudkin’s letter, of course); but honestly, what sort of sense does this sentence make? The IUD referred to is not intrauterine death but an intrauterine contraceptive device, or IUCD, and this “higher than but not inferior to” gobbledegook refers to a pre-set “non-inferiority” definition of >8% IUCD expulsion. The IUCDs in question were fitted at the time of first trimester abortion as opposed to 2-6 weeks later, and the study shows that by fitting IUCDs there and then, you get higher take-up rates but lose a few to early expulsion. That over-compressed sentence I quoted is very confusing and unnecessary: the NEJM editors have excellent taste in correspondence, but they do need someone to check their English; and I am ready and waiting and a mere two hours’ drive from Boston.

2235   It’s time for the sirtuins. This article promises to help you understand “ the biology that undergirds their promise as therapeutic targets.” Undergirds: with such delicious words plucked from the dictionary, maybe the NEJM doesn’t need my help after all. And here is the full magnificence of  NEJM artwork too, with lots of arrows doing very busy things inside mitochondria, and a text guaranteed to baffle all but the most diligent. So what are sirtuins then? Well, thingies that tend to make you burn up and die, and so the agents of ageing, perhaps. If you live long enough, you may one day find out.

Lancet  11 June 2011  Vol 377
2007   Anyone working in our profession must be appalled at the level of intelligence shown by the British schoolgirl. If they got any brighter there would be no male doctors at all. It is a matter of universal lament that there is hardly a single female medical school applicant who doesn’t have 5 top grade A-levels plus grade 8 in oboe and a track event record, never minding the fact that most have halved the infant mortality of a South African township or two in their gap year. Now here is a study suggesting that we need to give them more iodine to improve their IQs, urgently. If this is deficiency, Lord preserve us from sufficiency.

2013   Terutroban was an antiplatelet agent. So is aspirin. Servier did a big RCT hoping to show that terutroban might be better for the secondary prevention of cardiovascular events following stroke or TIA. It was not and the study was stopped early for futility; so goodbye terutroban.

2023   Doctors faced with sick patients often reach for a handful of steroids, but it’s often difficult to know whether they do good or harm. In this Dutch study, patients admitted with uncomplicated community-acquired pneumonia were randomised to receive intravenous dexamethasone or saline. The steroid-treated group left hospital a day sooner on average.

BMJ  11 June 2011  Vol 344
How long is a course of anticoagulation? Where I practised, it was either six months or indefinitely. Here is an analysis of individual participant data from 7 trials in venous thromboembolism which suggests that the answer may be three months in the case of events with a clear precipitant and indefinitely in the case of unprovoked VTE.

The primary care department at Oxford University has tolerated my presence for many years, though I have never been in a position to contribute much to its formidable record of important publications. Here is an exemplary attempt to examine the diagnostic value of laboratory tests in identifying serious infection in febrile children by a meta-analysis of seven studies. You will learn a lot about the difficult task of meta-analysing diagnostic studies if you read this paper slowly and in full – for example “It is easiest for clinicians to think of a positive result with a likelihood ratio of 2 as making it twice as likely that the patient has the disease. However, this is imprecise as the likelihood ratio applies to the change in odds rather than probability of disease— that is, the likelihood ratio×pre-test odds=post-test odds. So to calculate the precise impact of the test result on disease probability, it is necessary first to convert the pre-test probability to odds (pre-test odds=pre-test probability/(1−pre-test probability)) and then after multiplying by the likelihood ratio convert the odds back to probability (post-test probability=post-test odds/(1+post-test odds)).” David Mant, who oversaw this study, once spent time trying to explain this to me – probably the worst 20 minutes of his life. It is terribly important, but not the stuff of busy sessions full of sick kids. And there remains the stubborn fact that these studies tell us the odds which apply to hospital departments, not the places we may happen to be. So is there a take-home message? Well, forget about the white count. A very high CRP spells trouble – like you didn’t know. Procalcitonin? Probably good, but not available. More primary care studies are needed, as they say: and now it’s the new prof’s turn.

Ann Intern Med  7 June 2011  Vol 154
709    The Bayesian world of acute primary care is populated by people we half know, who have illnesses that we half diagnose, in periods that are half stress and half boredom, accompanied by cups of tea and unwholesome confectionery. Amongst the earaches and the babies who vomit at unfortunate moments, there is quite likely to be a young lady taking oral contraception who has stabbing chest pain and feels generally off. You get her to press on the spot and she says ouch. Is this a sufficient diagnostic test? What if she has a slight fever? Am I compiling a Wells score? Should I do a D-dimer? Frankly I have no idea, so I suppose I better had. The orderly Dutch, who do things so much more thoroughly, should be our guide in such matters: here they compare the performance of four clinical decision rules in combination with D-dimer “in the diagnostic management of acute pulmonary embolism”, according to the title. I don’t know why they put it in this clumsy fashion: what they mean is to safely rule out PE. All the decision rules they look at – Wells rule, revised Geneva score, simplified Wells rule, and simplified revised Geneva score – are equally good rule-outs when combined with D-dimer in hospital emergency departments.

719    It’s called original research, but it’s not as if you really needed a new cohort study to tell you that women smokers get peripheral vascular disease. Still, a useful reminder that treatments for nicotine addiction are amongst the most useful interventions you ever prescribe: far more beneficial than most of the statins and antihypertensives you spend your day handing out to healthy people.

752    So how do our British death panels actually work? I’m going to keep this excellent account of NICE and its modi operandi on my memory stick, because I intend to sell my expertise to the Sarah Palin nomination campaign when it meets in New Hampshire in September. And also the next one on p.756 on cost-effectiveness as assessed by our much admired national body, even though it has now been stripped of its direct rationing powers. 

Plant of the Week: Fagus sylvatica “Pendula”

This is a traditionally a tree for large spaces and wide vistas, such as country parks. But the scale of buildings in the science area of Yale, where we currently live, is such that you can quite comfortably fit a weeping beech tree between them and let it grow to impressive American arboreal standards. Like elephants, these trees manage to be both massive and homely. Moreover they have splendid grey bark, and well, yes, they also have trunks.