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Richard Lehman’s weekly review of medical journals

Richard Lehman’s journal review—26 January 2015

26 Jan, 15 | by BMJ

richard_lehmanNEJM 22 Jan 2015 Vol 372
331 “Approximately one in four extremely premature infants born at 22 to 28 weeks of gestation does not survive the birth hospitalization; mortality rates decrease with each additional week of completed gestation.” I am not your best guide to this topic, but for those who want to know more, a new study maps trends in the survival of these babies in the USA. The data span from 2000 to 2011 and the 22,248 babies were born in study hospitals within the US National Institute of Child Health and Human Development Neonatal Research Network. I don’t know how typical these hospitals are, but the results differ from the UK Perinatal Mortality Survey in that their deaths from infection have gone down whereas ours have gone up. In both countries, overall mortality has shown a modest fall, but deaths from necrotising enterocolitis have risen.

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Richard Lehman’s journal review—19 January 2015

19 Jan, 15 | by BMJ

richard_lehmanNEJM 15 Jan 2015 Vol 372
201 “The main challenge is to ensure better systems [of sharing data] for the future. Because ‘the optimal systematic review would have complete information about every trial—the full protocol, final study report, raw dataset, and any journal publications and regulatory submissions, ‘a prospective system of research governance should insist on nothing less… These changes have been long called for, and delay has already caused harm. The evidence we publish shows that the current situation is a disservice to research participants, patients, health systems, and the whole endeavour of clinical medicine.” more…

Richard Lehman’s journal review—12 January 2015

12 Jan, 15 | by BMJ

richard_lehmanNEJM 8 Jan 2015 Vol 372
113 A vaccine that works really well is the best kind of medical intervention. But a vaccine that gives partial protection is a headache. Sanofi Pasteur has developed a tetravalent vaccine which is 60.8% protective against symptomatic dengue in children in Latin American countries where dengue is endemic. It is least effective in serotypes 1 and 2 and most effective in serotypes 3 and 4, and it is a distinct improvement on previous experimental vaccines against this increasingly common flavivirus. There is a huge market to be tapped, but is this product ready for prime time? The accompanying editorial is very informative on the science but non-committal on the billion dollar question. more…

Richard Lehman’s journal review—5 January 2015

5 Jan, 15 | by BMJ

richard_lehmanJAMA 24-31 December 2014 Vol 312
2659 The effects of extreme heat on older adults: what a great topic for this cold gloomy time of the year. “Heat wave periods (are) defined as two or more consecutive days with temperatures exceeding the 99th percentile of county-specific daily temperatures,” and in this US study they were matched to non–heat wave periods by county and week. This study went right down from the top of Maine to the bottom of Texas, which may account for its rather weak conclusion: “Among older adults, periods of extreme heat were associated with increased risk of hospitalization for fluid and electrolyte disorders, renal failure, urinary tract infection, septicemia, and heat stroke. However, the absolute risk increase was small and of uncertain clinical importance.” more…

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…

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