Richard Lehman’s journal review – 31 August 2010

Richard LehmanJAMA  25 Aug 2010  Vol 304
    The first paper in JAMA comes from Denmark for a second week running, meaning that I have to rummage through Hamlet yet again for a suitable quotation. But alas (poor Yorick), I can find nothing at all about antiviral drugs used in pregnancy. I can’t even find anything related to birth registration or congenital defects, though I’m sure Shakespeare must have put them somewhere in this all-embracing work. Anyway, you’ll gather that we’re talking here about shingles treatments used in pregnant Danish women, who are all on an enormous national database. Aciclovir and valaciclovir used in the first trimester of pregnancy are not associated with any increase in birth defects, while too few women used famciclovir for us to be able to tell.
890    When our practice took part in Anthony Harnden’s ground-breaking studies of pertussis in the community, we were amazed to find that about one in four adults with persistent cough showed a recent antibody response to pertussis. The cough can go on for six months or more, and classically it comes in unstoppable paroxysms with long cough-free intervals between. The latest episode of the Rational Clinical Examination series confirms that these features are moderately predictive, and that whooping and vomiting are also useful pointers in children, but that no combination of clinical findings is actually diagnostic for pertussis. You make the diagnosis – usually after any treatment is useful – by per-nasal swab or PCR or antibody assays. We have just had our local access to antibody testing withdrawn on grounds of cost; but although testing does not allow a cure, at least it  gives a diagnosis and spares further investigation.

NEJM  26 Aug 2010  Vol 363
    You don’t look at papers on metastatic melanoma to get cheered up – the mean survival time is usually around 8 months – but there’s a definite glimmer of sunshine in this study. It’s odd that the NEJM didn’t run this paper alongside the one on ipilimumab for MM last week. That treatment resulted in a few long-term survivors and a few drug-related deaths: here there are more 18-month survivors and no treatment-related deaths. The drug is an oral agent which currently rejoices in the code name PLX4032, and it inhibits a key melanoma oncogene, encoding the serine-threonine protein kinase B-RAF. Most melanoma cells carry this mutation and the drug homes in on them like a Messerschmitt 109, attacking the B-RAF. Unfortunately most of the cells learn to take evasive action sooner or later, but this is a definite breakthrough.

820    If you have autosomal dominant polycystic kidney disease, your kidneys grow and form cysts under the influence of rapamycin (mTOR) pathway. It happens that the immune suppressant drugs sirolimus and everolimus inhibit the mTOR pathway, so a Swiss and a German team have carried out randomised trials on the two agents to see if they would delay progression in PKD. Sirolimus does nothing, while tacrolimus shows some slowing of kidney volume accretion but has no effect on declining renal function. A nice idea, but a failure so far.

852   In fact there are lots of nice ideas about in the treatment of mendelian disorders, though they are all quite tough to follow. When I first tried to download the PDF of this review about them, I got a scrambled version with the words “Nonsense-mediated mRNA decay” poetically marooned between Ljobt f ;!Bolf o{ zn f lu buusbot gf !b!qi and !Czqbt t !pgdbluf sn jobcpo!dpeo!czlu. The unscrambled version isn’t that different in places: I particularly commend to your attention the section on Hutchinson-Gilford progeria syndrome and the role of the enzyme ZMPSTE24. But really, one does need to engage with some of this stuff: for example, genomic understanding of pathological pathways may be leading to the development of a drug which slows down the progression of severe life-threatening Marfan’s syndrome by 90%. Some of the future of medicine genuinely lies in this direction.

Lancet  28 Aug 2010  Vol 376
   Trastuzumab got its commercial name Herceptin from the fact that it inhibits human epidermal growth factor receptor 2 (HER2). Its use in advanced breast cancer has triggered much debate about cancer drug rationing, and that’s bound to continue now that the ToGA trial has shown that it can also prolong survival in advanced gastric and gastro-oesophageal junction cancers which express HER 2. The trial was paid for by F Hoffmann-La Roche, whose pricing policy means that the drug costs about £55K per life-year gained: which, as the editorial states (p.659), “reiterates the important moral question – what is the justification for introducing a treatment that might enable one individual to live a few months longer, but will consume, for each person treated, the total yearly health expenditure of scores of their fellow citizens?”

705    “Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial” is not the sort of title to get people crowding around and spilling coffee on you in an attempt to read over your shoulder. But it might just mean a doubling in the success rate of treatment for hepatitis C. The agent is a direct antiviral called boceprevir. If you need to know more, you’ll have to read the paper (but don’t all rush at once, and mind that coffee), plus the accompanying editorial.

   Gestational trophoblastic disease is a British success story, based at Charing Cross and Sheffield; survival is 98.5%, and if you want to know the detail, read this review. It’s just odd that we haven’t learnt more from this shining example in the centralised treatment of rare cancers, and that other countries have been slow to follow the British example.

  The relationship between endometriosis and infertility is hard to understand, and the somewhat effortful English used by the three French authors does not always help. The main burden of their review seems to be that surgery works best when deployed early, rather than as a last resort after medical treatment has failed. “When age, ovarian reserve, and male and tubal status permit, surgery should be considered immediately so that time is dedicated to attempts to conceive naturally”. What a splendidly French idea, this dedication: consacrez-vous à l’amour, mes amis!

BMJ  28 Aug 2010  Vol 341
    Going psychotic in Hong Kong cannot be a pleasant experience for anyone concerned, as there isn’t really enough room; and preventing relapse after a first episode is a worthwhile aim, other things being equal. So this well-conducted double-blind trial of continued quetiapine versus placebo is an important contribution to the slender archives of evidence-based psychiatry. After full recovery from their initial psychosis, four-fifths of people given placebo had a relapse; in those who continued quetiapine, this was reduced to two-fifths.

437   Another important research paper in this week’s BMJ (I can’t really believe I’m writing this) deals with the hoary question of how soon to try again after a miscarriage. As most of you will know by now, the old wives’ tale that you should leave it a while is completely wrong: here is strikingly good evidence from Scotland that the sooner you get on with it, the better the outcome.

439    Patients newly diagnosed with type 2 diabetes are often in a state of shock, and the advice they receive can be quite bizarre, as you will see if you go to Healthtalkonline. Nice DESMOND tries to put that right: he consists of a six-hour structured group education programme, aimed at reducing weight and encouraging exercise and an appropriate diet (insofar as we know what that is). This study aims to show that Desmond is worth his money. Well, kind of, if you play around with the QALYs; but you have to agree with the correspondent who wrote in to say that “The difference of 1.1kg in weight, though statistically significant, is not, frankly, terribly impressive.”

444    Some excellent Clinical Reviews have appeared in the BMJ recently and this one on evaluating the child who presents with an acute limp is one of the very best. The lessons are not new – I first learnt them from the works of J Crawford Adams, which appeared in the mid-1950s – but they are vitally important, and here they are backed up with evidence and very clearly set out. Consider the age, look carefully at the hip, follow the modified pGALS examination set out in Box 2. Don’t ever take chances and miss septic arthritis or a slipped upper femoral epiphysis.

Plant of the Week: Sphaeralcea incana

This is the time of year when members of the mallow family come into prominence: in fact Richard Strauss wrote a fifth autumnal Last Song called Malven. But although the sphaeralcea belongs to the mallows, this little shrub is spring-flowering in its native habitat in hot North American deserts.

Our garden is as unlike a hot North American desert as can be; no sand and rattlesnakes here, just wet clay and slugs. Yet this plant is thriving and waving its orange flowers gaily over its attractive wrinkled grey leaves. It’s been doing this for months, after coming through the harsh winter unscathed. A must for a sunny spot in every garden.