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Richard Lehman’s weekly review of medical journals

Richard Lehman’s journal review—22 December 2014

22 Dec, 14 | by BMJ

richard_lehmanNEJM 18 December 2014 Vol 371
2353 Try to make winter bearable by thinking of the joys of late spring, such as seeing laburnum trees in full blossom. But you need to have plenty of garden space for the brief show they provide, and you also need to warn children against their poisonous seeds. This poison binds to the nicotinic acetylcholine receptors, which, as their name implies, are also the receptors that nicotine binds to. That is why laburnum extract has been sold as an aid to stopping smoking ever since the 1920s, under the name cytisine. Apparently, it is still available in some eastern European countries, but elsewhere we prescribe its vastly more expensive derivative, varenicline. I applaud the NEJM for publishing this open label New Zealand trial in which cytisine was compared with standard nicotine replacement therapy for smoking cessation. It was better. With vaping and cytisine becoming widely available, I really cannot see why combustible tobacco products should remain on the market. more…

Richard Lehman’s journal review—15 December 2014

15 Dec, 14 | by BMJ

richard_lehmanNEJM 11 December 2014 Vol 371
OL The clones! The clones! There is something of Edgar Allen Poe about this study, which describes how “clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death.” “Heh, heh,” whispers Vincent Price, “come and look at my clones. No, wait, they are YOUR clones! They lie in wait for you, death lies in wait. Your death. Farewell, my friend. The blessings of old age are necessarily mixed with fear.” But although the NEJM kindly makes this paper freely available to all, together with an editorial about Clone Wars, we are not about to see a new epidemic of haematological malignancies in older patients: we will just understand them better and probably devise new poorly predictive tests to worry people more. A second study spells out the same message. more…

Richard Lehman’s journal review—8 December 2014

8 Dec, 14 | by BMJ

richard_lehmanNEJM 4 December 2014 Vol 371
2227 “We need to remember that these drugs also have toxic effects, they are enormously and inappropriately expensive, and they haven’t cured anyone yet. It is premature to be opening the victory champagne bottles.” Yes, this editorial refers to a new drug class for cancers—the ALK inhibitors. But it applies across the board for new cancer drugs, as I pointed out over the last month. Their average cost is just short of $10 000 per month and the mean survival gain from them is 2.1 months. The annual production of champagne is 312 million bottles, which at an average wholesale price of say $30 would fetch about $10bn. So, unless I have got a nought wrong, you could buy up the word’s supply of champagne for the equivalent of 100 000 months of new cancer treatment, or enough to treat 10 000 cancer patients to extend their last year of life by two months. When Chekhov lay ill in the south of France, his doctor came up to his room with a bottle of champagne. “It’s a long time since I drank champagne,” said Chekhov, and died. Perhaps patients with metastatic cancer should be given the choice between a year of novel therapy or 4000 bottles of champagne. more…

Richard Lehman’s journal review—1 December 2014

1 Dec, 14 | by BMJ

richard_lehmanNEJM 27 November 2014 Vol 371
2061 Antoine Bernard-Jean Marfan (1858-1942) was a French paediatrician who lived in the happy era of medicine when you could affix your name to new signs, symptoms, laws, and syndromes, and Marfan bagged at least one of each for himself. But, ironically, his name is immortalised by a syndrome distinctly different from the one he described—a fate which has also overtaken Drs Alzheimer and Asperger. Marfan (pronounced to rhyme with enfant) presented a girl with arachnodactyly and digital contractures, whereas Marfan (to rhyme with bar-fan) describes a hereditary disorder of connective tissue without contractures. In the full blown form of this autosomally dominant condition, the leading cause of death is cardiovascular disease, mainly progressive aortic root dilatation and dissection. To prevent this, beta-blockers have been generally used since an open label trial showed survival benefit in 1994. But theoretical reasons have been put forward that angiotensin receptor blockers might work better, and this trial pitted atenolol against losartan. At the end of three years, in 608 subjects aged 6 months to 25 years, there was no detectable difference between the agents. The primary outcome was a surrogate—the aortic root z score. And the trial was not adequately blinded. Be that as it may, it is good to note that in both groups the aortic root actually decreased in diameter as the study progressed. more…

Richard Lehman’s journal review—24 November 2014

24 Nov, 14 | by BMJ

richard_lehmanNEJM 20 November 2014 Vol 371
1963 The melanoma trials last week got me thinking about how the current model of cancer drug research lets down trial participants and dying patients. Between 2002 and 2014, there have been 71 drug approvals by the Food and Drug Administration (FDA) for the treatment of metastatic and/or advanced and/or refractory solid tumours. The median gain in survival provided by these is 2.1 months. I discovered these figures in an excellent paper in JAMA Otolaryngology–Head & Neck Surgery, a journal that some of you may not read. I don’t know how it got hidden there. more…

Richard Lehman’s journal review—17 November 2014

17 Nov, 14 | by BMJ

richard_lehmanNEJM 13 November 2014 Vol 371
1867 “Metastatic melanoma remains just over the border of curability. As we wait and hope for some breakthrough in an agonizingly incremental process, there will be more trials like this one,” I wrote last week about a paper in JAMA. They haven’t been long coming. The two in this week’s printed New England Journal represent the highest standards in the field, which I find less than encouraging. In this first one, funded by F. Hoffmann–La Roche/Genentech, the primary outcome measure was progression free survival, but oddly this was assessed first by the investigators themselves and only afterwards by an independent review panel. I could not find any reference to investigator blinding. Anyway, the conclusion of this trial, in which 495 patients were recruited at 135 sites around the world, is that “the addition of cobimetinib to vemurafenib was associated with a significant improvement in progression free survival among patients with BRAF V600–mutated metastatic melanoma, at the cost of some increase in toxicity.” There was no significant effect on mortality at nine months. Now at present, metastatic melanoma is a certain death sentence, and the median age of the patients was 55, ranging from 23-88. So these patients were mostly facing a severe curtailment of their lifespan, and they volunteered to receive a treatment that might significantly worsen the quality of the short life remaining to them. Our response to their courage and altruism should be to ensure that trials of this kind are interpreted from the viewpoint of the patient, rather than the pharmaceutical company trying to obtain a licence for a new drug. Individuals themselves should be able to judge how a “significant improvement” in disease progression might be weighed against “some increase in toxicity.” The best way to achieve this would be for F. Hoffmann–La Roche/Genentech to release their full datasets and meta-data to independent analysts, including an advisory group of patients with metastatic melanoma. more…

Richard Lehman’s journal review—10 November 2014

10 Nov, 14 | by BMJ

richard_lehmanNEJM 6 November 2014 Vol 371
1771 The first paper in the New England Journal this week describes a French trial of rituximab versus azathioprine for maintenance in ANCA associated vasculitis. “At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio, 6.61; 95% confidence interval [CI], 1.56 to 27.96; P=0.002). Hence, to avoid one major relapse, 4 patients (95% CI, 3 to 9) had to be treated with systematic rituximab infusions rather than with azathioprine.” Now that’s good reporting, but why so few patients? It’s because ANCA associated vasculitis, first described by Friedrich Wegener in 1936, is quite rare. I went on a miserable detour to find out why Wegener’s name became detached from his granulomatosis. He spent the years 1939-44 as an SS pathologist adjacent to the ghetto at Łódź, where 250 000 Jews were crammed in to die from hunger, disease, overwork, or maltreatment, or sent to nearby Chełmno or more distant Auschwitz to be gassed. One thousand survived. So few records remain that it is impossible to prove that Wegener was guilty. Or innocent. Outside the ghetto at Łódź, 120 000 of the city’s Polish inhabitants are also thought to have died. Plenty of work for a pathologist, then. more…

Richard Lehman’s journal review—3 November 2014

3 Nov, 14 | by BMJ

richard_lehmanNEJM 30 October 2014 Vol 371
1685 The treatment of childhood and adolescent cancer is territory that most of us don’t trespass on, but we’ll need to go there this week just to have something to read about. JAMA is taking a Halloween break and the others seem to be going into an end of year lull. Anyway, here’s a less is more type study of how much cord blood you need for stem cell transplantation in haematological malignancies. This cord blood is precious stuff, and its use is limited by the finite number of haematopoietic progenitor cells that can be collected from a placenta. So it’s good to know that one unit of it may be better than two: “Survival rates were similar after single unit and double unit cord blood transplantation; however, a single unit cord blood transplant was associated with better platelet recovery and a lower risk of graft versus host disease.” In fact, the Kaplan-Meier chart shows that 35% of children in the single unit group and 40% of children in the double unit group died within two years: these are still very nasty diseases. more…

Richard Lehman’s journal review—27 October 2014

27 Oct, 14 | by BMJ

richard_lehmanNEJM 22 October 2014 Vol 371
1577 The whole point about tuberculosis is that it is slow. The discoverer of its causative organism, Robert Koch, called it the fungus-germ, or Mycobacterium. It takes 20 times longer to divide than most other bacteria. It is only after years of division that it can do terrible things. The old Welsh chest physicians I once worked for called this “galloping” TB, and recalled how it had carried off some friends of their youth. But even this word, when pronounced as “gahl-lopin” in a soft south Welsh accent, had a mournful slowness about it. Three trials in this week’s NEJM show that it does not pay to take shortcuts with this slouchy beast. Several new fluoroquinolone drugs kill off Mycobacterium tuberculosis quite rapidly in the laboratory and in animal models and were thought to offer the promise of a faster cure than standard rifampicin based regimens. In the first trial, moxifloxacin was tested in a randomised trial cunningly designed by academics based in the tiny windswept town of St Andrews in the Scottish kingdom of Fife. They spread their net across four continents, but they have shown that in uncomplicated, smear positive pulmonary TB, four months of a moxifloxacin based regimen is not dependably curative. more…

Richard Lehman’s journal review—20 October 2014

20 Oct, 14 | by BMJ

richard_lehmanNEJM 16 October 2014 Vol 371
1507  I hate military metaphors for cancer as much as anybody, but here is a study which describes hell in the leukaemia trenches. The 30 patients in the trial had acute lymphoblastic leukaemia. The youngest was 5 years old; most were under 20. All of them had relapsed after initial chemotherapy, which heaven knows is bad enough. Eighteen had then endured the horrors of allogeneic stem cell transplantation, and then relapsed again. Some had been through other experimental treatments. Now they were given an infusion of autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector. In all of them, this caused a cytokine release syndrome, which was severe in over a quarter of cases and had to be treated with the anti–interleukin-6 receptor antibody tocilizumab. The complete remission rate at the end of all this was 90%. So victory at a high price: the challenge now is to operationalise this treatment in a way that is bearable to patients and affordable to health systems. more…

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