Richard Lehman’s journal review—11 November 2013

Richard LehmanNEJM  7 Nov 2013  Vol 369
1783   When you’ve already tried dasatinib and nilotinib, should your thoughts be turning to ponatinib? In case you’re wondering what I’m talking about, these drugs are tyrosine kinase inhibitors and are used to treat chronic lymphatic leukaemia, and acute lymphatic leukaemia if it is Philadelphia chromosome positive. Ponatinib has been hailed as a major advance because it produces a response in many patients who have relapsed taking the other two, or who have had too many adverse effects: this phase 2 trial confirms that over a median period of 15 months. The editorial purrs with pleasure: “(the study) also provides support for a new drug-discovery paradigm leading from rapid ascertainment of new resistance mechanisms to targeted agents to equally rapid creation of molecules to address these mechanisms and rapid advancement of such compounds into clinical use.” Just two small difficulties. This drug is priced at $130,000 per year; and it caused major arterial thrombosis in 9% of patients over a year and a quarter. If you’re cool with cancer drugs that nobody can afford and that have devastating harms which only come to light after fast-track licensing, then that’s wonderful. It’s the new paradigm.

1807   Priced at about a ninth of the cost of ponatinib, dolutegravir is the latest integrase inhibitor to be marketed for the treatment of HIV. In the conclusion of the abstract (drafted by GSK) we read: “Dolutegravir plus abacavir–lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz–tenofovir DF-emtricitabine.” The “safety profile” consisted of a mixture of reversible side-effects, 7% less common with dolutegravir, and the higher effectiveness consisted of achieving a HIV-RNA level less than 50 copies per mm in 88% of patients at 48 weeks, as opposed to 82%. The clinical significance of this in the long term is hard to know. It’s interesting (to me—you may find it boring) that the manufacturer realized that a drug costing $14K for a year’s treatment is never going to sell in the poorer countries where HIV is a major problem, so it chose 139 centres in 13 rich countries to recruit an average of 6 patients each. I know I’m not alone in believing this strategy—widely seen in industry trials—has more to do with marketing than with science.

1819   Now some sound and simple British observations. The authors linked data from all children born in Britain between 1992 and 2008 after assisted conception without donor involvement with data from the United Kingdom National Registry of Childhood Tumours to determine the number of children in whom cancer developed before 15 years of age. Result: no association found.

JAMA  6 Nov 2013  Vol 310
1809   Faced with a patient in hypovolaemic shock, should you replace fluids as crystalloid or colloid? Don’t ask me; I probably couldn’t even find a vein. I am only scraping the barrel to find something to write about this week. In fact, don’t ask anybody, because nobody knows the answer, and the CRISTAL trial provides no resolution. Conducted in a highly pragmatic manner—open label, using any colloid locally available—in five Francophone countries, it failed to show any significant difference in 28-day mortality.

1829   Testosterone is the root of all evil, according to some. Or else it is the essence of manly life. Both, probably. You can find any number of websites touting the benefits of testosterone replacement therapy and there is an active “low T” advertising campaign in the USA. It is a relatively evidence-free area, and in my view it remains so after this study, which compared outcomes in men with low testosterone and coronary heart disease who were given testosterone to outcomes in the majority who were not. The authors looked at 8709 US Armed Forces veterans who presented for coronary angiography and happened to have had their testosterone measured and found to be lower than 300 ng/dL (about 11 nmol/L). Of these, 1223 started testosterone therapy after a median of 531 days following coronary angiography. At a mean follow-up of three years, these men had a higher rate of death, myocardial infarction, and stroke. But there is simply no way to adjust for all possible dissimilarities between these groups.

1837   Surgeons, as we know, have superhuman powers. Their testosterone levels are probably off the scale. They do not need sleep like ordinary mortals. The last of these actually seems to be true: Canadian surgeons who operated in the wee small hours (between midnight and 7 a.m.) and then went on to do daytime elective cholecystectomies achieved the same results as if they had been in bed the night before. Oh, and 17% of them were testosterone deficient, due being female.

Lancet   9 Nov 2013  Vol 382
This week it’s The Lancet’s turn to have nothing for the ordinary generalist—not that the other journals are exactly bursting with riches. A trial which discovers how best to ration HIV treatment in African children makes ironic reading after the GSK/ViiV Healthcare trial puffing dolutegravir at $14K per annum. There are a couple of grand global surveys of disease burden in categories so vague that it’s hard to know what they signify: “illicit drug use and dependence” and “mental and substance use disorders.” And the clinical reviews are about conditions there are no effective treatments for: primary sclerosing cholangitis and tinnitus.

BMJ  9 Nov 2013  Vol 347
Neonatology is scary stuff that most of us would prefer not to think about. However, it’s worth knowing the bottom line of this systematic review and meta-analysis of published data on the role of nasal continuous positive airway pressure (CPAP) initiated at birth for prevention of death and bronchopulmonary dysplasia in very preterm infants. The conclusion is stated with admirable clarity: “One additional infant could survive to 36 weeks without bronchopulmonary dysplasia for every 25 babies treated with nasal CPAP in the delivery room rather than being intubated.”

Pardon my scepticism, but I don’t think we will ever find the magic intervention that will stop sick elderly people needing a lot of help and institutional care. Telecare, self-efficacy interventions, and coordinated care plans may actually provide people nearing the end of their lives with a slightly better level of support, but it will never stop them ending up in hospital or nursing homes. If there is a moral case for providing a better quality of life for people who are old and in bad health, we had better get used to the fact that it will cost money and that its benefits will be very hard to measure against complex patterns of inexorable decline. Two hospitals in Nottingham and Leicester tested the use of an acute medical assessment unit for stays of up to 72 hours, and further outpatient management by specialist physicians in geriatric medicine, including advice and support to primary care services. Result: no measurable change in outcomes or in the use of secondary and residential care. Maybe primary care nurses and doctors, who have worked with these elderly people for decades, are already quite good at their jobs.

Ann Intern Med  5 Nov 2013  Vol 159
577    If you are over 15 and have a sore throat, ask yourself if you have the following:

  • History of fever
  • Tonsillar exudates
  • Tender anterior cervical adenopathy
  • Absence of cough

This is the CENTOR score: four points and you get antibiotics; one point and you don’t, because it’s highly unlikely that you have a streptococcal infection. This study carried out in retail clinics in the USA (where everybody is very strep aware) concludes that if Americans with sore throats were asked to score themselves before coming to a doctor, it could save several hundred thousand consultations each year.

Fungus of the Week: Lactarius deliciosus

The main season for this woodland mushroom is generally earlier, but I did manage to find a few in the last couple of weeks. This is a dubious pleasure. It is always nice to find something to take home after a hunt in the woods, but these orange lactarii of modest size are often soggy and full of larvae, and even when they are not, they taste mainly of cardboard. The generic name Lactarius means that they exude a milky sap, which quickly turns a greyish green colour in the case of this species, making it pretty unmistakable; the specific name deliciosus is simply a lie, made up by the fungus marketing department.

So when you return home to present your finds to a sceptical spouse, you have two options: bin the lot, or devise a recipe which makes them taste nice. If you decide upon the latter, there is no time to lose. Were you to keep the sound-looking specimens in the fridge overnight, they would probably be crawling with little maggots by the morrow. So put them on dry newspaper in a warm place for a couple of hours to take away some of their moisture, and then cook them as follows:

Chop up smoked streaky bacon or pancetta into cubes of about 1cm (less in the case of thick pancetta). Put butter in a frying pan and start frazzling the bacon. Chop an onion fairly finely and add, together with a couple of cloves of garlic. Now add the mushrooms and keep the heat high: they are bound to exude liquid and you want most of it to evaporate. When they are cooked, add cream and keep the heat up for it to boil for a minute or so. Sprinkle with finely chopped parsley and chives; maybe a spot of tarragon if you are feeling that way inclined.

You can serve this on its own, perhaps on toast, or as an accompaniment to roast chicken or even white fish. Cooked thus, the cardboard mushrooms will have absorbed the flavours of the bacon, herbs and cream and will provide a woodland undertone of their own. Almost worth picking them for.