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Richard Lehman’s weekly review of medical journals

Richard Lehman’s journal review—1 September 2015

1 Sep, 15 | by BMJ

richard_lehmanNEJM  20-27 Aug 2015  Vol 373

726   We start with a basket trial. Say you are in a supermarket and put lots of brown things in your basket—bread, a joint of lamb, a tin of brown beans, some kiwi fruit, and a shirt. Now, out of scientific curiosity, you decide to dip the contents of your basket in anti-brown, a corrosive substance that binds to anything that’s brown. You find that the bread dissolves completely, the lamb turns blue, the kiwi fruit explodes, the shirt shrinks and the beans remain unaffected. The actual basket trial described here was only slightly more sophisticated. It gathered together 120 patients with various forms of non-melanoma cancers, all of which expressed the oncogene BRAF V600. They were all given a selective oral inhibitor of the BRAF V600 kinase, vemurafenib. The short-term responses were then observed. “Preliminary vemurafenib activity was observed in non–small-cell lung cancer and in Erdheim–Chester disease and Langerhans’-cell histiocytosis… There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab.” more…

Richard Lehman’s journal review—27 August 2015

27 Aug, 15 | by BMJ

richard_lehmanNEJM 6-13 Aug 2015 Vol 373

503 Outcomes in early breast cancer surgery just keep on getting better. But between 20-40% of patients who have a partial mastectomy need to undergo further surgery soon afterwards because the excision margin shows possible tumour involvement. A team at Yale decided to see if this could be averted by routinely performing a further shave of the cavity margins after all grossly visible tumour had been completely removed. Randomization—either to close the wound or to perform extra shaves—occurred at the moment of decision during the operation. And sure enough, those who had the extra shave were half as likely to need re-excision surgery, and had no increase in complications.


Richard Lehman’s journal review—3 August 2015

3 Aug, 15 | by BMJ

richard_lehmanNEJM 30 July 2015 Vol 373
405 This week’s first paper has an interesting title: Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function. It’s the first time I’ve seen the word “therapeutic” used to describe something done to a person who is already dead. The hypothermia they refer to here occurs in a newly deceased cadaver. The currently recommended alternative is to maintain heat in the cadaver until the kidneys are harvested. This is what it means when it says “after declaration of death according to neurologic criteria, donors were assigned by means of computer-generated block randomization to mild hypothermia (34 to 35°C) or normothermia (36.5 to 37.5°C).” So it’s the whole body and not just the kidneys: I’m labouring the point because it took me a few minutes reading the paper to work it out myself. The result of the trial shows that cooler is better. It was stopped early at the point when delayed graft function had developed in 79 recipients of kidneys from donors in the hypothermia group (28%) and in 112 recipients of kidneys from donors in the normothermia group (39%) (odds ratio, 0.62; 95% confidence interval, 0.43 to 0.92; P=0.02). more…

Richard Lehman’s journal review – 27 July 2015

27 Jul, 15 | by BMJ Group

richard_lehmanNEJM  23 Jul 2015  Vol 373

307   Four summers ago I found myself dabbling in the early history of outcomes research. I was astonished to find that surgeons over a century ago were reflecting on much the same issues as they do today. In cancer, for example, there was lively debate about the place and timing of radiotherapy in relation to surgical procedures. Here’s a study of regional node irradiation in early-stage breast cancer, which recruited between the years 2000 and 2007. Ionizing radiation was first used to treat cancer in 1896 and this trial shows that we are still learning how to use it. The median follow-up here is 9.5 years, and irradiating the regional lymph nodes as well as the breast made no difference to the primary outcome, which was overall survival. It did, however, reduce the recurrence rate of breast cancer by an absolute margin of 5%, at the cost of a small difference in the occurrence of lymphoedema (absolute increase 3.9%) and pneumonitis (1%). more…

Richard Lehman’s journal review—20 July 2015

20 Jul, 15 | by BMJ

richard_lehmanNEJM 16 July 2015 Vol 373
209 I’ll say it again: “Cancer boasts the worst trials in medicine. Also the worst drug regulation. Also the worst cost/benefit ratio for new treatments. And also the worst drug toxicities. Plus the highest levels of public and charitable funding. My forehead hits the desk when I read about this stuff.” I’m developing quite a lump. Here’s a Pfizer funded trial of palbociclib, a new add-on last ditch treatment for breast cancer, which has become resistant to anti-hormone treatment. Don’t bother with the abstract which just obscures the findings. The editorial gives the results in a nutshell: “The rate of objective response with palbociclib–fulvestrant (10%) was not much higher than the rate with placebo–fulvestrant (6%), but the rate of clinical benefit (response or prolonged stable disease) at 6 months was significantly higher with palbociclib–fulvestrant (34%, vs. 19% with placebo–fulvestrant). There was no significant between-group difference in overall survival, but it is too early to expect such a difference.” But the “clinical benefit” referred to is just a temporary halt in the growth of the cancer, while “palbociclib adds considerable cost and toxic effects, including mechanism-based myelosuppression, some fatigue, nausea, and an increased risk of infection.” So what is the place of this drug in clinical management, and how does this trial help us make decisions with women who are dying of end stage breast cancer? No idea. Expect much more of this kind of thing now that the 21st Century Cures Act has been passed in the US and the Saatchi Bill is being relaunched in the UK. Palbociclib is not a cure. It isn’t low hanging fruit. It is unripe fruit. And if you eat unripe fruit, you get stomach pains and diarrhoea. If you use unripe drugs, you harm people and give yourself brain pains and logorrhoea. more…

Richard Lehman’s journal review—13 July 2015

13 Jul, 15 | by BMJ

richard_lehmanNEJM 9 July 2015 Vol 373
111 First they defined a new disease category. Then they promoted a mechanistic explanation. Then they made everyone focus on the pathway that matched the latest drugs. Then they made billions of dollars selling the drugs. By the time the whole edifice started to look shaky, everybody was complicit and nobody wanted to admit they had been fooling themselves and their patients. Just think of any condition that interests you. Does this ring true? Alas, it almost certainly will, wherever you look. Take the kind of chronic lung deterioration which is labelled Chronic Obstructive Pulmonary Disease. A lot of the disease isn’t actually obstructive, but we’ve been led to believe that it necessarily involves accelerated deterioration of pulmonary function which is best tracked by measuring the forced expiratory volume in 1 second (FEV1). A group of investigators, funded by an unrestricted grant from GlaxoSmithKline, decided to see if this is what actually happened in three cohorts of adults who had their FEV1 measured over a number of decades. And lo! half of them started off with a low FEV1 in early adulthood and then showed a subsequent mean decline in FEV1 which was no faster than normal, despite the same smoking exposure as those who showed accelerated decline. So there are two fundamentally different subclasses of COPD, which probably need fundamentally different approaches to management. And I bet if you look in most areas of medicine, you’ll find the same gross ignorance about natural history.


Richard Lehman’s journal review—6 July 2015

6 Jul, 15 | by BMJ

richard_lehmanNEJM 2 July 2015 Vol 373
11 Liraglutide for weight loss. Like the second Iraq war, we knew for years that it was coming. The propaganda was laid out well in advance. “Obesity is a chronic disease with serious health consequences,” say the NovoNordisk authors. No it’s not, it’s a measure of body weight that carries certain risks. Likewise “pre-diabetes,” which is a blood level that in the majority of people does not lead to diabetes. And diabetes too is just an arbitrarily defined risk cluster, not a weapon of mass destruction. Moreover, if we are going to medicate every fat person in the Western world, we need long term outcome data, not just evidence of a drop in blood glucose and BMI. This 56 week trial recruited 3731 “patients” at 191 sites in 27 countries. Why? You could easily find that number of “patients” with BMI >30 (or >27 if at elevated risk) in any small township in the developed world. Nearly 80% of the people recruited were women. Why? “The sponsor, Novo Nordisk, planned and performed the statistical analyses, [and] provided editorial and writing assistance.” Why? Because everybody does it and the FDA doesn’t mind. Liraglutide will undoubtedly get its licence for use in weight reduction. Three mg daily would currently cost about £200 per month in the UK, and there are at least 15 million Britons who would meet the recruitment criteria of this trial. I make that a potential NHS bill of £36bn annually. Some NICE bargaining lies ahead. Let’s hope they will insist on long term outcome data, with a close look at the cost/benefit ratio and potential harms. more…

Richard Lehman’s journal review—29 June 2015

29 Jun, 15 | by BMJ

richard_lehmanNEJM 25 June 2015  Vol 372

2533  The research articles in this week’s print NEJM are all about arcane stuff I’ve covered previously. The Clinical Practice article takes us back to the real world—the one we’d rather not think about, where there is a smell of urine and random cries from rooms down the corridor. How would you like to be cared for if you get advanced dementia? I would like to be in institutional care, and not be a burden to those I love. I would not want to be given antibiotics and I certainly wouldn’t want to be fed artificially. I wouldn’t like to think that my family would have to argue about such things, time and again. But alas, the real world is appallingly bad at caring for people who are dying of dementia. Looking back, I shudder at my complicity in this. “Mrs Bannister’s got a UTI with two plusses of protein and nitrates (sic). Can we have a prescription faxed to Boots?” The printer started whirring before the second sentence was finished. And it’s the same the world over. “In SPREAD, 75% of suspected infections were treated with antimicrobials, but less than half of all treated infections and only 19% of treated urinary tract infections met minimal clinical criteria for the initiation of antimicrobials.” I wish this article was open access, because it would be a fine addition to any Choosing Wisely library. more…

Richard Lehman’s journal review—22 June 2015

22 Jun, 15 | by BMJ

richard_lehmanNEJM 18 June 2015 Vol 372
2387 For the first time in years, I actually handled a new printed copy of the NEJM last night. What a suave production it is! Flicking though its stylish pages with their subtle sheen, I came across the IMPROVE-IT study once again. It’s a telling reminder of how credulous the medical community can be when faced with a slick presentation of something it wants to believe. No mortality benefit from ezetimibe in over 16 000 very high risk patients over six years. But a borderline significant benefit in a catch-all composite endpoint. Astonishing! Paradigm shift! more…

Richard Lehman’s journal review—15 June 2015

15 Jun, 15 | by BMJ

richard_lehmanNEJM 11 June 2015 Vol 372
2307 Here at last is a study that shows some benefit from out of hospital cardiopulmonary resuscitation. It’s not a randomised trial, since that would be considered unethical, or at least heretical. Instead it comes from interrogating a big Swedish database of outcomes following cardiac arrests outside hospitals. “CPR was performed before the arrival of emergency medical services in 15 512 cases (51.1%) and was not performed before the arrival of EMS in 14 869 cases (48.9%). The 30 day survival rate was 10.5% when CPR was performed before EMS arrival versus 4.0% when CPR was not performed before EMS arrival.” Meanwhile, a big Japanese survey shows that there has been an improvement in outcomes there since resuscitation in the community dropped the “kiss of life” and moved to a strategy based on chest compression only. more…

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