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Richard Lehman’s weekly review of medical journals

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…

Richard Lehman’s journal review—13 October 2014

13 Oct, 14 | by BMJ

richard_lehmanNEJM 9 October 2014 Vol 371
1381  With blood transfusion, it seems that less is usually better. This has been shown in renal patients and palliative care, and is now reconfirmed in septic shock. Fifteen years ago, the Canadian Critical Care Trial Group study showed that transfusing critically ill patients at threshold of 10 G/dl of haemoglobin produced worse outcomes than using a threshold of 7. Now Scandinavian triallists have gathered and randomised 1000 patients with septic shock in 32 general ICUs in Denmark, Sweden, Norway, and Finland: a logistic feat to be wondered at. They have shown that a threshold of 7 is as good as a threshold of 9, saving gallons of blood. In fact, it halves the amount of blood used. more…

Richard Lehman’s journal review—6 October 2014

6 Oct, 14 | by BMJ

richard_lehmanNEJM 2 October 2014 Vol 371
1285  Here is a trial which had me taking my glasses off and scratching my bald patch. Why on earth should a drug company—in this case Boehringer Ingelheim— want to pay for a trial of taking patients OFF a drug? And why in particular should it want to take people with chronic obstructive pulmonary disease off inhaled steroids while keeping them on a long acting beta-adrenergic agent (LABA), when we know that LABAs increase mortality unless you take them with an inhaled steroid? The latest evidence for this came in JAMA a couple of weeks ago. more…

Richard Lehman’s journal review—29 September 2014

29 Sep, 14 | by BMJ

richard_lehmanNEJM 25 September 2014 Vol 371
1189  This week we start with mepolizumab. Before we know it, we encounter losmapimod. Enough is enough. I think the World Health Organization should convene an extraordinary meeting of the International Nonproprietary Names Committee with the sole purpose of Stopping Silly Names. Medical practitioners are serious people and they should not be expected to trade in nonsense words. When humanized monoclonal antibodies were new and few, it might have made sense to end all their names in zumab, but now there are so many nobody can remember which is which. Mepolizumab is targeted against interleukin 5. The first of two trials in severe asthma with sputum eosinophilia shows that it allows a useful number of people to avoid the regular use of oral corticosteroids or to reduce their dose. In the 24 weeks of the trial, the rate of adverse effects was the same as placebo. more…

Richard Lehman’s journal review—22 September 2014

22 Sep, 14 | by BMJ

richard_lehmanNEJM 18 September 2014 Vol 371
1100  The way I have ureteric colic is so classical that just watching me sweat and groan is enough for anyone to make the diagnosis, even without the haematuria on the dipstick. I see the same thing all the time in out of hours primary care patients, and generally get the diclofenac injection drawn up after about two sentences of history taking while I dip the urine. I can’t remember ever having to refer anyone for acute imaging. But somehow acute nephrolithiasis manages to cost the US healthcare system $2bn a year, and it seems that most patients are investigated with an immediate abdominal CT. This is a dangerous procedure, partly because of the radiation load, but even more because of all the incidental findings that are bound to turn up. A large American trial compared CT with point of care ultrasound or full formal ultrasound. “Initial ultrasonography was associated with lower cumulative radiation exposure than initial CT, without significant differences in high risk diagnoses with complications, serious adverse events, pain scores, return emergency department visits, or hospitalizations.” I suspect that if they had had a no-investigation arm, the results would have been the same. more…

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