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Richard Lehman’s weekly review of medical journals

Richard Lehman’s journal review—14 April 2014

14 Apr, 14 | by BMJ

richard_lehmanNEJM  10 Apr 2014  Vol 370
OL   A deadly virus has been conquered. Hepatitis C genotype 1 can be cleared with a simple oral combination treatment, and compared to that, the rest of this week’s medical news seems minor. So I will start by running through the hepatitis C papers which have just appeared on the NEJM website. It you want to read them all, they are free, but as most of you are not virologists or hepatologists, you may just want the bottom line. The names to conjure with are: ledipasvir and sofosbuvir on the one hand, and ABT-450, ritonavir, and ombitasvir on the other hand. Now that you have memorized these, I shall continue. The first of these combinations underwent three trials funded by Gilead Sciences, all of them outstandingly successful. Cure rates of 94-99% were achieved within 12-24 weeks with or without the addition of ribavirin, whether or not patients had received previous treatment or had hepatic cirrhosis. more…

Richard Lehman’s journal review—7 April 2014

7 Apr, 14 | by BMJ

richard_lehmanNEJM  3 Apr 2014  Vol 370
1287   Multitarget stool testing, you will be pleased to hear, is not the most important topic in the NEJM this week. There is in fact so much else on the NEJM website that I could take up the whole review dealing with nothing but online papers. So let us quickly dispose of these crap tests. There is a new one which includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. This was compared with a standard immunochemical stool test (FIT). Both were used on nearly 10,000 people at average risk of bowel cancer, who all underwent full colonoscopy too. “Multitarget stool DNA testing detected significantly more cancers than FIT did, but had more false positive results.” The old screening dilemma revisited: progress does not lie this way.


Richard Lehman’s journal review—31 March 2014

31 Mar, 14 | by BMJ

richard_lehmanNEJM  27 Mar 2014  Vol 370
1189   I sing the body mitotic: we are a mass of cells dividing, mutating, cannibalizing, spreading. The wonder is not that we ever die of cancer, but that we often don’t. Cells which become aggressive are extraordinarily versatile at remaining aggressive, as shown by the relatively rare ALK-Rearranged Non–Small-Cell Lung Cancer. This accounts for about 5% of non small cell lung cancers, and its invasiveness seems to be caused by mutations of the anaplastic lymphoma kinase gene (ALK). So the majority of these tumours show an initial response to crizotinib, a drug which inhibits ALK. But the nasty fact is that within a year, the cells no longer respond. A new ALK-targeting drug is ceritinib, the subject of a phase 1 trial reported here. It is promising: “Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK.” But having learnt habits of aggression, those cells may yet prove deadly. Ceritinib is described as “20 times as potent as crizotinib against ALK” in this Novartis-sponsored trial, but that figure means nothing in itself. The proof will be in the phase 3 trial.

Richard Lehman’s journal review—24 March 2013

24 Mar, 14 | by BMJ

richard_lehmanNEJM   20 Mar 2014  Vol 370
1091    Please follow these instructions carefully: 1. Remove half of the skull, taking care to ensure you have chosen the appropriate side. 2. Repair the dura over the swollen brain and replace the scalp. 3. Wrap the removed skull and place in a refrigerator, choosing a shelf free of food items. 4. When the brain has returned to normal size, replace the half skull with care to ensure a good fit. That’s my idea of a hemicraniectomy, though I may have got some details wrong. I leave these things to others, like the neurosurgeons of Heidelberg, Ulm, Berlin, Leipzig and Dresden who conducted the DESTINY II trial. Hemicraniectomy was performed on 49 patients of mean age 70 for malignant middle-cerebral-artery infarction, i.e. total MCA occlusion causing unilateral massive brain oedema. Compared with 63 controls, these patients showed a much higher rate of survival without severe disability, though the majority of survivors still needed assistance with most bodily needs.

Richard Lehman’s journal review—17 March 2014

17 Mar, 14 | by BMJ

richard_lehmanNEJM  13 Mar 2014  Vol 370
1029 Doctors, by and large, make bad scientists. We train our minds for years in some of the hardest intellectual disciplines, and then make do with the sloppiest excuse for thought when it comes to believing what we wish to. All of us learned, at some time between the ages of five and fifteen, that just because something happens after something else, it doesn’t mean that the first thing caused the second. The whole endeavour of medical research is to get beyond post hoc, propter hoc. And yet we go back to square one with embarrassing regularity. We deploy a device for frying renal nerves and are awe-struck at the 30+mmHg drop in BP that follows. Then we do the same thing by random allocation and blinded follow-up, and the drop turns out to be less than 10mm. Five years ago, a special report appeared in the New England Journal describing a 36% drop in post-surgical morbidity and mortality in a “global population” following the introduction of surgical checklists. In three of eight sites, the intervention made little difference, but in others there were reductions in adverse outcomes of 30-50%. Soon surgical checklists became mandatory in whole countries and regions. Now, guess what? The introduction of mandatory checklists turns out to have made no difference in some places, as shown by this special report from Ontario. Whereas in another before-and-after report, from a neurosurgical unit in Finland, it made an impressive difference. That’s life, guys: science begins where “look at these numbers, you gotta do this” leaves off. In fact the science which is most likely to tell us about how checklists work or don’t work is not numerical at all, but descriptive and ethnographical. more…

Richard Lehman’s journal review—10 March 2014

10 Mar, 14 | by BMJ

richard_lehmanNEJM  6 Mar 2014  Vol 370
901    The cat and mouse game of man versus human immunodeficiency virus has just taken a new turn. HIV kills off CD4 T cells by binding to the CCR5 receptor. Now if you could manufacture CD4 T cells without a functioning CCR5 receptor, the virus would not be able to bind to them, and might go into a sulk. You would need billions of these T lymphocytes, of course, and they might need topping up from time to time. This seems to be what happened in an experiment on 12 volunteers with HIV who stopped their antiretroviral treatment four weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified to switch off the receptor. The modified cells had an estimated mean half-life of 48 weeks. As hoped, they proved resilient against HIV: the details are complex, but this approach seems worth a lot more enquiry.

Richard Lehman’s journal review—3 March 2014

3 Mar, 14 | by BMJ

richard_lehmanNEJM  27 Feb 2014  Vol 370
799    I’ve reached the age when people look back and sigh and cluck about the way the world has changed since they were children. In the 1950s, the world was actually a pretty nasty place, and at any moment the hydrogen bomb might bring it to an end. People with three copies of chromosome 21 were known as “mongols” and they were generally put in “homes” where they typically died before the age of 40. As medical students in the early 1970s, we had to be told to refer carefully to “Down’s syndrome” rather than mongolism. Amniocentesis in the second trimester was the only means of prenatal diagnosis. Since then, the means to detect and abort trisomic pregnancies have gradually improved, with chorionic villus sampling and nuchal thickness scanning, and various blood tests. I learn from this paper that they include first-trimester serum markers such as pregnancy-associated plasma protein A (PAPP-A) and free beta subunit or total human chorionic gonadotropin (hCG), and second-trimester serum markers such as maternal serum alpha-fetoprotein (MSAFP), hCG, unconjugated estriol, and inhibin. But at the same time, the lives of people with Down’s syndrome have become longer and happier, as they receive proper care and integration into society. So: to abort or not to abort? That is the question, and morally I think it has become more difficult. Technically, though, it has become a lot easier, with the coming of massively parallel sequencing of cell-free DNA (cfDNA testing) in maternal plasma. This US study shows that it is much less likely to throw up false positives for trisomy in low-risk pregnancies than conventional testing. But I don’t envy the parents who are faced with a positive result. more…

Richard Lehman’s journal review—24 February 2014

24 Feb, 14 | by BMJ

richard_lehmanNEJM  20 Feb 2014  Vol 370
699   This week, the NEJM is big on bevacizumab. Amongst the crowd of mabs, this is one of the best known: Avastin is a humanized monoclonal antibody directed against vascular endothelial growth factor-A which has been on the market since 2004. It has had its ups and downs, and this week is both a down and an up. Down goes any hope that it could be a useful first line treatment for newly diagnosed glioblastoma, even though these tumours tend to be highly vascular. This trial and the one that follows fail to show any useful effect from adding bevacizumab to standard treatment with temozolomide and radiotherapy.

Richard Lehman’s journal review—17 February 2014

17 Feb, 14 | by BMJ Group

richard_lehman NEJM

599 Most weeks I quote you the conclusion of some pharma-funded trial which overstates the benefit of an intervention. But in reality clinical trials of any kind can be a form of marketing: doing them is difficult work, there are reputations and ideas at stake, and the temptation to overstate results is always there for career academics as well as for pharmaceutical marketing departments. And I really admire the work that went in to the Multicenter Selective Lymphadenectomy Trial (MSLT-I) for melanoma, which commenced in 1994. Twenty years on, we are told that “Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas.” more…

Richard Lehman’s journal review—10 February 2014

10 Feb, 14 | by BMJ

richard_lehmanNEJM  6 Feb 2014  Vol 370
513   Now that I’ve moved to a policy of including online first articles in these reviews, I’m immediately confronted with a problem: I’ve already told you about most of the content of this week’s NEJM, and there isn’t much new on the website. Never mind. Here is the companion piece to the rotavirus study from last week. In that one, there wasn’t a clear signal that monovalent (as opposed to pentavalent) rotavirus vaccine was associated with a tiny risk of intussusception, but in this somewhat larger study, there is. Which is a pity.

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