Last year my wife was called to attend for breast cancer screening. Seeing the spectre of “small shadow” -> “inconclusive histology” -> “extended lumpectomy” -> “still not sure”, playing out in my mind, I suggested that it may be wiser not to attend. Of course she ignored me and of course a small “probably a calcified node” was found. She attended for a targeted biopsy whilst I got on with another endoscopy list. To my surprise she phoned after the biopsy to ask me to pick her up as she felt unable to drive home!? When I collected her she described how they had spent an hour, repeadedly poking deep into her breast with an increasingly blunt biopsy needle. She had been locked into some sort of frame to keep her still in the X-ray machine. Once freed from this fixation device, she collapsed on the floor with a vaso-vagal attack. She apologised for fainting and vomiting on the floor of the X-ray department and asked if there was anywhere to lay down and recover. Cheerfully the staff assured her that this happened all the time and that she may just as well stay on the floor as there were nowhere else to recover! Seeing all my worst fears coming true, I anxiously waited for the histology (which I was sure would be inconclusive). Luckily histology was a clear-cut calcified tiny lump and the screening programme scored another “success”. The tenderness and bruising lasted a month.
Most screening programmes were started with little evidence as they simply seemed a good idea. Unfortunately, after a screening programme has been launched, there is no way of determining if it is doing any good. The reason for this includes “lead-time bias”, “length-bias” and “healthy volunteer bias”. Take screening for Barrett’s dysplasia as an example. We have done it for decades without a shred of evidence. The brave “UK BOSS trial” is turning the clock back and will hopefully provide some evidence in support.
If the benefit of a screening programme is not confirmed (by a prospective randomised trial) before it is launched, sooner or later concerns about expense, lack of benefit or even harm may start to emerge. Without solid trial evidence gathered before launch, costs may become difficult to justify and the issue of benefit vs. harm impossible to weigh up.
Breast cancer screening is a good example. A Danish review (BMJ 2010;340:c124), found that the mortality of breast cancer was falling at a similar rate in both screened and unscreened women. A year later, a retrospective analysis looked at the breast cancer mortality in Europe to compare the timing of the reduction in countries starting screening at different times (BMJ 2011;343;d4411). The authors concluded that screening did not seem to play a direct part in the reduction in breast cancer mortality. Fifteen years ago, the same concerns were put forward regarding screening for early gastric cancer by Tony Axon (Lancet 1998;351:1350-2).
Luckily, screening for colorectal cancer has been thoroughly studied. We all know that a centrally organised, National comprehensive screening programme reduces an individual’s risk of dying from colorectal cancer. Surprisingly, I did not have a reply at my fingertips when a patient asked me, “OK, I understand that my lifetime risk of dying from bowel cancer is 1:50 but what will my risk be if I now send my poo off for testing ?” With the UK guaiac FOB kit, presumably the answer is 1:75?
You may be surprised to hear that 25 years ago, my wife got my genes checked out. This was in a pilot screening trial open to pregnant women searching for the “delta 508 mutation” responsible for most cases of Cystic Fibrosis in the UK. A month later, we were surprised to hear that she was a carrier. Subsequently, I tested negative for the delta 508 mutation. I thought that this was reassuring but the research team was less clear-cut in their assessment; “We are not sure about the CF mutations which occur in Scandinavians…”, “there are hundreds of mutations which can all cause the disease…”, “you may have some other mutation which will interact with your wife’s mutation…”, The risk of your child being born with cystic fibrosis is probably no greater than 1:300… we hope“.
Rapid DNA sequencing using powerful machines has now brought down the time and cost so that a complete map of your DNA can be delivered for less than $1000 and within just a few days. The problem is that we don’t have the faintest idea of what the data means. Furthermore, the “epigenetics” of how genes are silenced and switched on, in response to environmental triggers, is also unknown. Interestingly, the setting of these switches can be transmitted to our children and grandchildren! Perhaps the reason why your wife is afraid of dogs is that her great grandmother was bitten by one?
Naturally, enthusiasts are lining themselves up to praise the rapid march of the technology from research bench, to clinical practise and soon the supermarket checkout. Nobody has paused to consider than having someone’s complete genome sequenced opens a can of worms; “Did you know that you carry these 20 lethal recessive genes?” “Another 350 of your genes have been linked to Alzheimer’s, early heart disease or rapidly progressive cancer or psychiatric disease” “but we think that some of these risk may only be of relevance if you have red hair or eat a lot of bacon or marry the wrong person”, “Sorry but we can’t advice you any further”. “We should now really screen your partner and your children and your children’s children“.
The screenee will suddenly have many legitimate questions; “Will this data be cross matched with other databases such as the insurance industry, the police or International Research databases – “for the benefit of others?” Will I have any say in this? One thing is certain, once your genome has been entered into the “DECIPHER Consortium database” or the “Leiden Open Variation Database” or the “Locus Reference Genomic Collaboration database” (to mention just a few) you will spend your remaining life completing lifestyle forms and replying to upsetting letters asking if you have noticed any chest pains, deterioration in memory, suicidal thoughts or any funny lumps in the last 6 months.
Finally, I am resolved not to accept a blood transfusion unless my life depends on it. This is not because of any religious convictions. My concerns are twofold; first there is evidence from our armed forces that liberal transfusion of wounded on the battlefield leads to worse outcomes. In fact, soldiers who get shot “in theatre” (this is what the military calls the dusty backstreets where wars are nowadays fought) receive just enough fluids to have a detectable radial pulse. During the helicopter transfer to the nearby field hospital they get their blood analysed by “thromboelastography”, to guide red cell+/-plasma+/-platelet replacement to replenish oxygen carriage and pre-empt coagulopathy. Within an hour they undergo “Damage Limitation Surgery”.
The outcomes are impressive as fewer than 10% of soldiers die from their injuries. In contrast, patients with a bleeding upper GI lesion are managed with liberal transfusions, not guided by anything (at least not thromboelastography) and the “emergency endoscopy” is carried out sometime in the next 24 hours! The outcomes are less than impressive in that you are more likely to die from a bleeding ulcer in the suburbs than of a high velocity bullet in Helmand.
Apart from worsening outcomes associated with liberal transfusion, there is also ”Transfusion-related immunomodulation” (TRIM) to consider. Forty years ago, it was discovered that patients who had previously received a transfusion where far less likely to reject their renal transplant (NEJM 1973;5:253-9). The reason for this is that donor white cells somehow damage immune systems causing impaired natural killer cell function, decreased phagocytosis and suppression of lymphocyte production and antigen presentation. This is one of the reasons why transfusion services are trying to remove as many white cells as possible.
Another reason is the outbreak of “new variant Creutzfeld-Jacob disease” (nvCJD) in the UK. To prevent the spread of “prions”, virtually all our endoscopy accessories are now disposable and certain operations such as tonsillectomies are no longer carried out. In 2004, a study (Lancet 2004;364:527-9) confirmed that the condition could also be transmitted by blood transfusions. The UK government has now banned anyone who have received a blood transfusion since January 1980 from donating blood. Most other countries have gone further and have banned blood donations from anyone who set foot in the UK between 1980 - 1996. Even sperm donations are banned!
How the mysterious “prion protein” causes our brains to rot is unknown. But it makes me wonder, what other mysterious proteins, currently floating around in seemingly healthy blood donors, remain to be discovered?