Richard Lehman’s journal review – 7 November 2011

Richard LehmanJAMA  2 Nov 2011  Vol 306
1874   The older you get, the more likely you are to have a haematological malignancy, and the less likely you are to be able to stand up to the rigours of myeloablative therapy followed by allogeneic haematopoietic cell transplantation, which can offer a cure in younger patients. You might think that total myeloablation was essential to the success of donor bone marrow grafting, but in fact it is not: some at least of the effect is mediated by a graft versus host reaction. So it might be possible to use half-dose radio-ablation and still get some survival benefit from cell transplantation: and this is confirmed in a multinational trial which enrolled 372 patients aged 60 to 75. Their five-year survival was 35%. Mind you, the treatment is not particularly pleasant, and the frequency with which graft-v-host reactions occur means that many patients have to take long-term steroids with a range of adverse effects.

1884    Here is an analysis of breast cancer risk in relation to alcohol intake from the 106,000 women in the US Nurses’ Health Study. Between 1980 and 2008, their alcohol consumption was recorded on 8 occasions, and there were 7690 incident cases of breast cancer. Sadly, the analysis shows that even slight consumption raises the risk of invasive breast cancer: in fact alcohol seems to be carcinogenic to the female breast in a dose-related manner. Gentlemen sharing a bottle with ladies should see to it that they have most of it.

NEJM  3 Nov 2011  Vol 365
1663   Those of you who have read Atul Gawande’s book Better (and that should be all of you) will remember a chapter on cystic fibrosis which describes how truly aggressive, insistent treatment can improve outcomes. To me, this is not a welcome message. It means that patients have to live lives dominated by their illness; and as someone said when Leonard Cheshire was awarded the Victoria Cross for repeatedly flying low and fast through German air defences as a bombing pathfinder, you can’t operationalise something that deserves the highest honour for valour. We need a routine treatment for cystic fibrosis that will improve outcomes for everyone irrespective of exceptional effort. Ivacaftor may or may not be this treatment: but it certainly marks a new step in the search for one. It pains me to admit it, but this is an actual success for genomics-led, bench-to-bedside pharmacology. The gene for CF was discovered in 1989; the most common mutation is ΔF508-CFTR, but for some reason the pharma boffins have been more successful at targeting a much rarer defect in G551D-CFTR, present in fewer than 10% of people with CF. For this subset, ivacaftor is strikingly successful in improving lung function over 48 weeks. It also reduces sweat sodium and prevents infective exacerbations. If such promise can be maintained in the long term, through the use of this and other targeted drugs, CF may become compatible with near normal life expectancy and even with leading a nearly normal life. 

1673   In this next paper, new ground-breaking science is used to combat the effects of existing ground-breaking science. We saw from the first JAMA paper this week that graft versus host disease (GVHD) is an almost inevitable problem when using allogeneic cell transplants. But what if you could simply kill off the allogeneic cells once they have done their job and start becoming a nuisance? A trial in five patients of a cell-suicide system to achieve this was a complete success. It’s a pretty amazing story: you take the cells that are going to cure the patient, in this case genetically modified T-cells for patients with relapsed acute leukaemia. Spliced into these cells is caspase 9 (iCasp9), which means that they will die as soon as they come into contact with AP1903, an otherwise bioinert small-molecule dimerizing drug. So if the T cells start replicating and causing GVHD, you simply inject some AP1903 into the patient and the T cells vanish. It seems to be as simple as that.

1702   I try to provoke comment in these reviews, but I seldom get any unless I attack people for pronouncing Clostridium difficile in the French manner. I won’t go there this time: the Consortium de Recherche sur le Clostridium difficile was set up by Canadians who prefer to speak French rather than English. Let them be as difficile as they please: one cannot reason with such people. In this very well-conducted study they determine the host and pathogen factors for colonization and infection in acute hospitals. The usual suspects are there amongst the host factors: age, antibiotics, and acid suppressing medication prior to admission. The chief pathogenic culprit in hospital infection is the strain of C diff known NAP1.

1713   Do you understand ulcerative colitis? If so, please step up and share your knowledge with us, since this comprehensive review only serves to show that nobody else does. I remember being puzzled as a medical student nearly 40 years ago that nobody seemed to know what causes so dramatic a condition, and we still seem to be at much the same stage of vague theorizing about abnormal reactions to the gut flora, coupled with auto-antibody formation in the form of circulating IgG1 antibodies against a colonic epithelial antigen that is shared with the skin, eye, joints, and biliary epithelium. As for treatment, surgery has improved a bit in the last 35 years, and physicians now have infliximab to use as a nearly last resort drug.

Lancet  5 Nov 2011  Vol 378
1627    This study comes from the intensive neonatal care units of Germany, where it has become common practice to slip a thin tube down the trachea and squirt a bit of surfactant into the airways of babies requiring continuous positive pressure ventilation, to prevent worsening respiratory distress syndrome and the need for intubation. Until now, nobody had put this method to the test of a randomised controlled trial. Now they have, and it works.

1635   And now – amazingly for The Lancetanother useful randomised trial addressing a useful clinical question: in removing a cutaneous melanoma more than 2mm thick, should the excision margin be 2cm or 4cm? The answer is that it does not matter.

BMJ  5 Nov 2011  Vol 343
I was a skinny kid because my parents were poor and I walked everywhere and didn’t get a lot to eat. Nowadays if your parents are poor you are more likely to grow up obese. Despite a huge amount of confident political assertion and a certain amount of research, we don’t fully understand the causes of childhood obesity and we certainly don’t know how to combat it. The diligent Swiss decided to have a go in two high-immigrant city school catchments, putting in four 45 minute exercise sessions every week and lots of teaching about healthy eating, sleep, and exercise. “Regardless of consent, participation in the intervention was mandatory for all children.” Gosh. Those who underwent the compulsory intervention got fitter, but at the end of the study their BMIs were no different from the control group.

Do mobile phones cause brain tumours? No, fortunately. This study examines the entire population of Denmark and finds absolutely no correlation between mobile phone subscription length and the incidence of brain tumours.

When the first successful trials of fixed-dose oral anticoagulants appeared some years ago, I suggested that their manufacturers should fix their prices so that they exactly equalled the current cost of warfarin and its complex system of INR monitoring. They did nothing of the kind, of course. So for the next fifteen years at least we will have a two-tier anticoagulation system: a lucky few will be allowed (or be able to afford) the new drugs and the rest will continue to queue up for regular blood tests. The quantitative harm-benefit part of this paper shows that the direct thrombin inhibitor dabigatran etexilate is clinically superior to warfarin; but the economic analysis suggests that for all but the highest risk patients, warfarin remains more cost-effective.

Ann Intern Med  1 Nov 2011  Vol 155
569    In the far-gone hippie era, there was a vogue for all things Indian: meditation, ragas, curry, and yoga. Of these, yoga was the most difficult and the first to fall out of fashion. But we were left with a vague feeling that if one persevered in twisting one’s legs in odd ways, one would achieve some kind of better karma and perhaps even better health. This British trial looks at the effect of a 12-week course of yoga on low back pain over a period of 12 months. Alas, it had no benefit, and the commonest adverse effect was worse back pain. Stick with curry and ragas, say I.

Plant of the Week: Araucaria araucana

Inside Yale’s Peabody Museum, a couple of hundred yards from where we live, there is a splendid collection of dinosaurs in a vast hall surrounded by a mural of life in the Cretaceous period. Repulsive huge reptiles stomp about a landscape dominated by volcanoes and forests of palm, gingko and monkey puzzle trees: all very thrilling. In the last year, a Cretaceous garden has been planted outside the museum, watched over by a life size bronze Torosaurus on a rough block of pink granite. Around him they have planted various trees of similar antiquity. There is also grass, which I first thought was a mistake, but it seems that grasses began to flourish in the age of the dinosaurs.

A week ago we had an unseasonal fall of snow, and the snarling Torosaur looked very impressive, with white drifts on his back and head, and a little gingko tree with its leaves turning golden beside him in the snow. Also standing by imperturbably was a tiny monkey puzzle tree, destined in time to become taller by far than the museum itself, let alone the dinosaur.

Do not, whatever you do, buy one of these baby araucarias in a nursery pot and stick it a garden bed. Probably the only circumstance in which the purchase of an araucaria can be deemed wise is if you own a large tract of land in Western Scotland which you intend to bequeath to your grandchildren. In that case, plant an araucaria forest with a ratio of six female trees to every male (but beware: they sometimes change sex in mid-life). In about 30-40 years they will bear copious crops of cones which will fall to the ground, yielding huge numbers of edible nuts. You will not live to see the day, but you will have started the Scottish nut industry, and history will record your name as a benefactor of mankind. Scottish history will, anyway.

I first read the story of how the monkey puzzle tree arrived in Britain in a book about Kew Gardens, which is currently gathering dust three thousand miles away. From memory, it runs thus. Captain George Vancouver set out with two ships to explore the west coast of northernmost America in 1791. He had mixed success since various Spaniards and Frenchmen had just beaten him to it, and on his way back in 1795 he took supplies in Chile, where he was entertained by the liberator Bernardo O’Higgins. This bit cannot be true, since Bernardo was aged 17 at this date, and had not liberated anywhere, though he did indeed go on to do both Chile and Peru. The gentleman in question must have been Bernardo’s father, Ambrosio Bernardo O’Higgins, born Ambrose Bernard O’Higgins in Sligo, but by this time ruling Chile on behalf of the Spanish monarch.

Feasting with O’Higgins, Vancouver was impressed with some strange nuts served near the end of the meal, and slipped a few into his breeches pocket. When he arrived back in London, he gave some to Joseph Banks at Kew Gardens. Banks carefully tried to germinate them under glass at Kew and when a young tree sprang from one of them, he tended it in the garden under a specially constructed glass pyramid. Nobody had seen anything like it. A few cuttings were taken from it and sold to the nobility for extravagant prices. But then disaster struck: high winds and snow destroyed the glass pyramid and the infant tree was left exposed to the British winter. Nobody then knew that this was a tree from the mountains of Chile and completely hardy to snow, wind and frost. It simply carried on growing, as its forebears had for 250 million years. It became one of the chief attractions of the garden, summer and winter.

In early life, the tree has a certain appeal, with its stiff branches covered in tough dark green scaly leaves. But in mere adolescence, it starts shedding leaves from the lower branches, which then stick out in ugly bareness and eventually drop off. As it moves towards adulthood, which can last 1,000 years, it becomes distinctly ugly, with a telegraph pole trunk reaching 30+m into the air, knobbed with branch scars and topped with a scrawny canopy of miscellaneous horizontal branches. Definitely a tree for the Scottish nut industry only.