Richard Lehman reviews the latest research in the top medical journals

NEJM 19 Apr 2018

Pembro plus chemo for non-small cell lung cancer

“There is at bottom only one genuinely scientific treatment for all diseases, and that is to stimulate the phagocytes.” These amazingly prescient words were written in 1906 by George Bernard Shaw and put into the mouth of Sir Ralph Bloomfield Bonington in The Doctor’s Dilemma. Remember that this was in the era before antibiotics, at a time when Ehrlich had only just suggested the idea of “magic bullets” to attack pathogens. But Shaw was talking about “all diseases,” and by phagocytes he meant more than just macrophages. I’m sure he would have loved the idea that 110 years later “phagocytes” (killer T lymphocytes) could be stimulated to eat cancers. Enter pembrolizumab. It prepares cancers to be eaten by other cells. A few months ago came evidence that it works better than standard chemotherapy for non-small-cell lung cancer which shows more than 50% expression of programmed death ligand 1 (PD-L1). It does this by unleashing the immune system on the cancer by eliminating the checkpoints that it has developed against lymphocyte attack.

In the latest trial it was used in combination with standard chemotherapy (pemetrexed and a platinum agent) on patients with the most advanced NSCLCs showing >50% PD-L1 expression. Compared with the addition of placebo in patients with metastases, pembro with chemo showed a marked effect on progression, raising the hope of long-term disease control. Many more trials will be needed, however, before we know the optimal regimen to combine checkpoint inhibition, which sets loose the dogs of war, with chemo, which tends to poison the said dogs.   

Gene cure for β thalassaemia

I’m sure Shaw also had advanced ideas about genetics in 1906. He had advanced ideas about everything and our hearts go out to the people who had to listen to them (see Michael Holroyd’s biography). However, he can’t have known about genes at that time, and he may not have known about β thalassaemia. Here is a disease that certainly cannot be treated by stimulating the phagocytes, but can now be cured by putting new genes into those worst affected. This is an extraordinary breakthrough and its benefits have proved persistent over two years and longer.  

“Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe β-thalassemia without serious adverse events related to the drug product.”

Ambulatory BP is most predictive

The GP practice I worked in was one of the first in the world to have an ambulatory blood pressure machine (in the early 1990s) and we kept on producing measurements which in those days we had no means of interpreting. It struck me that it would probably be another 20 years before we knew their prognostic significance. Well, the 20+ years have gone by and this is the conclusion: “Ambulatory blood-pressure measurements were a stronger predictor of all-cause and cardiovascular mortality than clinic blood-pressure measurements. White-coat hypertension was not benign, and masked hypertension was associated with a greater risk of death than sustained hypertension.” This analysis was based on a national cohort that included 63,910 adults recruited from 2004 through 2014 in Spain. “Masked hypertension” is the paradoxical phenomenon where blood pressure is normal in the clinic or office (<140/90 mmHg), but elevated out of the clinic (ambulatory daytime BP or home BP>135/85 mmHg). So it is the opposite of “white-coat” hypertension which itself carries a worse prognosis than sustained hypertension. Sustained high BP is much the commonest type, and so is associated with the highest number of deaths. Ambulatory monitoring helps us to pick out the outliers who need the most treatment, and who are invisible to the nurse in the GP surgery.

Rotavirus vaccine safe where most needed

The main danger associated with rotavirus vaccines in the past was intussusception, a weird made-up English word with a Latin ending. The actual Latin word for it is invagination. Too rude to use in front of the children, perhaps. Rotavirus kills children in Ethiopia, Ghana, Kenya, Malawi, Tanzania, Zambia, and Zimbabwe. All these countries now have vaccination programmes using the latest monovalent vaccines. They have also kept registries of intussusception to see if there was any difference between vaccinated and unvaccinated children. To the extent that these are dependable, there is no difference.

JAMA 17 Apr 2018

Choices for vaginal prolapse

I got a bit lost even with the title of this paper about 5-year follow-up after surgery for symptomatic uterine prolapse, but here is its message in a nutshell: “The estimated probability of surgical failure was 61.5% with uterosacral ligament suspension vs 70.3% with sacrospinous ligament fixation, a nonsignificant difference. Anatomic failure was 48% with perioperative behavioral therapy and pelvic floor muscle training and 49.5% with usual care, while Prolapse Organ Prolapse Distress Inventory scores improved by −59.4 points vs −61.8 points, respectively, signifying nonsignificant differences.” So women opting for these treatments should have low expectations, though a high proportion expressed themselves satisfied despite anatomical failure.

LDL-C lowering meta-analyzed

Twenty years of embroilment in the (quite unnecessary) statin wars has left me with a number of basic convictions, three of which are:

– LDL-C is a risk factor, but you should use LDL-C lowering drugs according to total cardiovascular risk, not LDL-C alone

– statins are for practical purposes the only LDL-C lowering drugs worth using

– it is pointless remeasuring LDL-C once it has been lowered by a statin.

Here’s a meta-analysis which questions the usefulness of statins in people with low baseline levels of LDL-C, defined as below 100mg/dl in the curious units used by Americans, or 2.4 mmol/L in the rest of the world. It is a marvellously thorough and well-illustrated analysis of 32 RCTs, which can’t be summarised in a few words, though it is worth quoting this sentence:” This analysis further supports individualizing estimates of the potential for a cardiovascular risk reduction benefit from LDL-C–lowering therapy based on consideration of not only a patient’s absolute risk and current LDL-C level, but also an individualized estimate of the risk reduction based on current LDL-C level and the outcomes desired.” Maybe.

JAMA Int Med Apr 2018

Hypoglycaemia: look at patients not hospital data

In primary care, we used to see sulfonylurea-induced hypoglycaemia in type 2 diabetic patients all the time, but very little of it reached hospital. The same is still true in America, according to a Kaiser Permanente database: “Surveillance of severe hypoglycemia in the United States is currently based on hypoglycemic events resulting in ED or hospital utilization recorded in the EMR. Although hypoglycemia-related ED visits or hospitalizations are rare (approximately 0.8%annually), self-reported severe hypoglycemia events are relatively common (approximately 12% annually). Based on our comparison of these two sources of data, we estimate that only approximately 5% of self-reported events among pharmacologically treated patients with diabetes are captured by healthcare utilization-based surveillance.”

Electronic consultations in primary care

Imagine a perfectly responsive health system. This was what Britain attempted 70 years ago, based on the concept that everybody would be registered with a doctor who would be on call every day and night throughout the year. The nation was bankrupt and full of bomb sites, but that didn’t matter: it would be paid for from general taxation. This was the right thing to do. Not many people had telephones, so they could knock on the doctor’s door. Fewer still had cars, so they asked for a home visit. Oh, and if they needed spectacles, or their teeth fixing, that would be free too. For 1948, this was an ideal National Health Service for everybody except GPs, who had to pay for cover if they ever wanted a single day or night off.

The workload of primary care is still the biggest obstacle to an ideal open health service. The 1948 NHS did not have a budget: it would cost whatever was needed. It was a statement about society’s duty to the sick. And so it remains, to the intense distaste of most modern politicians. All plans in 2018 are based on cost containment, not open medicine. And so we come to the question of how people should access their illness services. Obviously, it should be in the same way as they access most things: through smartphones or directly. This will not save costs or reduce the need for skilled professionals: quite the opposite. Get used to it. Nor is this about “health”: it is about what happens when health breaks down.

Primary care must open itself to electronic consultations and it’s amazing that we still fret about this in the 21st century. It is through well-grounded fear of overload without extra human resources, as this study from the USA shows:

“While associated with improved specialty care access, eConsult systems simultaneously created new challenges for PCPs, such as an increased burden of work in providing specialty care. Primary care practitioners varied in their enthusiasm for these workflow changes with diverging perceptions of the same processes.”

You will get much the same message if you read Trish Greenhalgh’s paper on UK experiences of electronic consulting:

“There are complex challenges to embedding video consultation services within routine practice in organizations that are hesitant to change, especially in times of austerity.” But if they could create an open health service in austere 1948, we can certainly do it in rich 2018: it is question of social will.

The Lancet 21 Apr 2018

Plasmodial perturbations

Speaking of the twenty-first century, how come there are two articles about malaria in The Lancet for 21 April 2018? Didn’t we get rid of that in the 1960s? Duh, no: we built thousands of multi-warhead nuclear missiles and landed a man on the moon instead. So the plasmodia survive to play hide-and-seek and kill about half a million people each year in hot, unimportant places. Nets and insecticides still play a major role in control. A study done in Africa, where mosquitoes show widespread pyrethrin resistance, finds that combining indoor residual spraying with pirimiphos-methyl and piperonyl butoxide (PBO) long-lasting insecticidal nets provided no additional benefit compared with PBO long-lasting insecticidal nets alone or standard long-lasting insecticidal nets plus indoor residual spraying.

For those wanting an update on malaria, there is also a review article which nicely covers all the basics. “The progress towards elimination in some countries shows that existing tools can be enough to eliminate malaria if the right conditions are in place: political commitment, access to health care, and adequate human and financial resources.” Again, it is a matter of social will.

The BMJ 21 Apr 2018

The artificial endocrine pancreas

The idea of a self-regulating insulin pump for treating type 1 diabetes is neat and intuitive and we all want it to happen. This article would have us believe that it has:

“Our systematic review and meta-analysis has shown that artificial pancreas systems are an efficacious and safe treatment approach for people with type 1 diabetes, leading to increased time in near normoglycaemic range, and reduced time in hypoglycaemia and hyperglycaemia. The results were verified for all types of artificial pancreas and in all sensitivity analyses.” But elsewhere the authors (most of whom have industry affiliations) allude to inconsistency in outcome reporting, small sample size, and short follow-up duration of individual trials. And then of course there is the question of long-term outcomes such as blindness, kidney failure, amputations, and cardiovascular disease. Unfortunately we’ll have to wait a bit longer to know how efficacious and safe these pumps really are, for the outcomes that matter most.

Plant of the Week: Vinca minor “Azurea Flore Pleno“

A few days of hot weather and everything becomes magical at this time of year in England. Our little back garden is full of scent from a big skimmia and osmanthus. The first clematis are about to flower.

Still, it is worth paying tribute to the low creeping things that appear unperturbably every year. I don’t mean the slugs, which seem to have taken a hit from the late frosts, but ground cover plants like the periwinkle in its many sizes and forms.

These can flower almost any time of the year, but our little double blue has only just started, and is as pretty a thing as you can find anywhere. While you wait for your precious hepaticas to produce one or two sky-blue flowers lasting a few days, these vincas produce lots which last for ages. You can plonk them anywhere and any bits you break will become new plants. Too easy? Invaluable, rather.