Richard Lehman reviews the latest research in the top medical journals

NEJM5 Jul 2018

And to finish with, would you like some cabozantinib?

You have run through the courses of your life, perhaps sooner than you would have liked. The first course was good health. The second started when someone found out you had hepatitis C. You still felt perfectly alright, but the third course began when your scans began to show fibrosis. You were on the point of getting potentially curative antivirals, but alas, course four was served up when they found of an area of hepatocellular carcinoma. Course five was surgery, and course six consisted of nasty chemotherapy with conventional drugs and/or sorafenib. But still it kept spreading. And now, instead of coffee, chocolates, and the bill, they are offering you cabozantinib. In this placebo-controlled trial of the latest tyrosine kinase inhibitor in advanced hepatocellular cancer, median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo. The rate of severe adverse events in the cabozantinib group was approximately twice that observed in the placebo group. Cabozanitinib for 10 months costs the NHS about £50K. Maybe we should be offering patients the choice between this drug and an 8-month luxury cruise: putting the nice into NICE.

Smallpox—the comeback and the cure?

Smallpox is a disease of terrifying infectivity and virulence: in the early 18th century one third of children in Europe died from it and many were left disfigured and/or blind. Despite its elimination from human circulation, there is a lingering fear that stocks of the virus remain, to be weaponised in a future conflict. That such stocks can kill was last demonstrated in 1978, a few hundred metres from where I now work in Birmingham; though the only time smallpox was actually used in warfare was probably in North America around 1760, by the British against native Americans fighting for the French. I guess there are at least two political leaders active today who might be stupid enough to risk killing 30% of the world’s population, so perhaps it’s good news that a drug now exists which would probably arrest smallpox infection, even when given after the first onset of symptoms. It is called tecovirimat and it cures monkeys of monkeypox and rabbits of bunnypox. It was compared with placebo in 412 healthy human volunteers and had no major adverse effects. If this is knowledge you ever need, the world will probably be coming to an end anyway.  

JAMA 3 Jul 2018

Cervical screening: HPV or standard cytology?

“Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months.” That’s the conclusion of the abstract of this Canadian randomised trial in 19,000 women. It may just be the heat getting to my brain, but I had to pause and decide whether this meant it was a good or a bad thing. That depended on what happened in those 48 months. You need to go to the text to find out: “in the first round of screening, significantly more CIN3+ cases were detected in the intervention (HPV tested) compared with the control (cytology only) group.” OK, so there were fewer cases at 48 months because more had been detected and treated in the first round. And that’s good. But that’s not quite all: there are various caveats and footnotes which you will have to go to the full paper to find out about. I get the distinct impression that we are in a transition period between screening strategies, and that HPV will win out.

Newer insulins, hypos, and hype

I am a very old man and you must attempt meaningful eye contact whilst I ramble. When I came into general practice there were just two basic kinds of insulin, called beef or pork. They worked perfectly well. Hypoglycaemia was common because venous blood sampling was the only way to judge control. But then home testing (still known as “doing a BM” in the UK, in honour of an early kit) became immensely popular, and human insulin analogues supplanted the old abattoir-derived products. Costs rocketed. Primary care nurse-led clinics proliferated: drug and device reps entered our surgeries, offering lots of freebies and sandwiches for learning sessions. But thanks to the NHS, patients didn’t have to pay for any of these expensive new products (the monitors and the sandwiches). Cut to 2009, a few months before I left GP partnership. I was looking for ways I might be useful in retirement and I leapt at the chance to tag on to John Yudkin on a visit to my hero Harlan Krumholz at Yale. In charge of the arrangements was a young diabetes scholar called Kasia Lipska who immediately became the target of John’s radicalizing zeal. How well he did his job! Here is her latest paper. Writing in a benighted country where a high proportion of people with diabetes cannot afford the only insulins available, she shows massive observational evidence that there is very unlikely to be any reduction in hypoglycaemia by using expensive newer analogue insulins (glargine or detemir) compared with the older NPH (neutral protamine Hagedorn) insulin.

JAMA Int Med July 2018

Carbs, insulin, and how we get fat

I like it that JAMA Internal Medicine has given space for a pair of articles about the carbohydrate-insulin model of obesity. It’s an attractive idea that most fatness and so-called type 2 diabetes is caused by too high an intake of food with a high glycaemic index. David Ludwig and Cara Ebbeling make a clear and detailed case for this, and it certainly beats the simplistic old idea that it’s just a matter of calories in and calories out, stupid. 

But three authors counter that this is just setting up a straw man (or Aunt Sally, but I won’t try and explain what that is), since nobody really holds that position and in fact the predictions of both these theories—the calorie-only and the carbohydrate-insulin—do not make predictions that work when tested. Unfortunately that just leaves us with a list of factors and nothing to build a best-selling diet book on. Not that that’s ever stopped anyone.

Catheter cataclysms

Wow! Here’s an article that has you thinking “why has nobody done this before?” It’s about the adverse effects of urethral catheters from the point of view of patients. And that may explain why you haven’t read it before—major journals often turn down even the best observational research about the experience of being a patient. Lucrative new molecules of uncertain benefit are much more exciting than living with illness. Living with an indwelling urinary catheter causes misery to 57% of those who do so, and non-infective complications are five times commoner than infective. This is based on the experiences of over 2,000 patients, and the non-infective complications include pain, blood in the urine, and a feeling of urgency. The full article is pay-walled but needs to be read by everyone who inserts catheters into women or men. In fact the finding should form part of a mandatory shared decision instrument for patients and health professionals prior to long-term catheter insertion.

The Lancet 7 Jul 2018

Going into ORBITA

I don’t suppose many readers spent Saturday afternoon reading The Lancet, but this week’s correspondence is a great example of the beautiful game. This is the one where Darrel Francis takes on the world and gets the ball in the back of the net. ORBITA, you may remember, was designed by Rasha Al-Lamee and the Francis team to demonstrate that in patients with single vessel coronary disease who were taking drugs for angina, stenting would produce better functional results at 6 weeks than a sham procedure. In fact it proved there was no difference. Some claim that Francis was offside, and cardiology star players are falling to the ground in agony in front of the referee. It is a time for cool heads. Will a yellow card be produced? Will the goal be allowed? It’s for viewers to judge, but I’d say that goal was good, David.

Too much acid, get out the bicarb?

In the shimmering summer air, I read the first line of this article as “Acute academia is often observed in critical illness.” Actually I misread “acidaemia”. A pity. Acute academia sounds like a good thing, but is rarely observed, since academia is by its nature a chronic condition. I suppose it has to be. This study—no doubt a couple of years in the planning—began recruiting patients in May 2015. It tells us that by and large, the urge to give sodium bicarbonate to sick patients with severe metabolic acidaemia should be resisted, since it makes no difference to clinical outcomes, though there may be a subgroup benefit in acute kidney injury. Chronic academia may produce a further answer in due course.

The BMJ 7 Jul 2018

How not to extrapolate

“Predicted lean body mass, fat mass, and all cause and cause specific mortality in men: prospective US cohort study” reads the title of this study, which uses an equation derived from the US National Health and Nutrition Examination Survey (NHANES) to predict outcomes in the Health Professionals Follow-up Study (HPFS). Oops. This can’t be done, as a researcher from the HPFS points out:

“None of the anthropometric variables used in the prediction equations were available in the HPFS. The HPFS contains only data on self-reported weight, self-reported height, and waist circumference measured at the umbilicus, a different anatomical site. Since the authors do not have the correct data to use in the prediction equations, the equations can’t be applied correctly. Calling the equations ‘validated’ is misleading because they were not validated for the anthropometric variables available in the HPFS.”  

Maternal virtue leads to leaner children

“Offspring of women who adhered to five low risk lifestyle factors (a high quality diet, normal body weight, regular physical activities, light to moderate intake of alcohol, and non-smoking) had a 75% lower risk of developing incident obesity than children of mothers who did not adhere to any of the low risk lifestyle factors.” For “women” read “female American nurses,” but I must grudgingly admit that this is probably true of the population at large. Grudgingly because the conclusion I feared then appears at the end of the article: “Our findings highlight the potentially critical role of maternal lifestyle choices in the etiology of childhood obesity and lend support to family or parent based intervention strategies for reducing childhood obesity risk.” Mmm. A bit more complicated than “choice” and “intervention strategies” I fear. Might obesity plummet if every mother was valued and supported in ways that made cheap comfort eating less likely? It’s a whole-society experiment or nothing, I think.

Plant of the Week: Lilium regale

The lily is so ancient an icon that it seems impossible that this greatest of lilies only entered British gardens a century ago. The purple-backed trumpets of one plant can scent a whole garden. It comes from Western China, delivered to these shores by Ernest Wilson who fell while collecting the bulbs and landed on a narrow pack-trail where he was passed over by a troop of mules laden with tea. His broken leg began to suppurate and it was two years before he could come home, one of countless men in those times with a “gammy leg” which drained pus from a sinus for the rest of their lives. It did not, of course, stop him from going back.

The lilies of the Bible are of an equally erotic mountain species:

“I am the rose of Sharon, and the lily of the valleys…My beloved is mine, and I am his: he feedeth among the lilies. Until the day break, and the shadows flee away, turn, my beloved, and be thou like a roe or a young hart upon the mountains of Bether.”