Dr. Eric Lim's Weblog

I was at the Royal society of Medicine in London a few weeks ago where a classic paradigm of lung cancer was discussed: when a patient with lung cancer presents with 2 nodules, how do you determine if they are synchronous or metastatic?

The premise for this question rests on the implications for further management. If the two nodules are synchronous, say 2 lesions that are T1 N0 M0 and T1 N0 M0 then it is assumed that complete resection of both will lead to a survival of a T1 N0 M0 tumour. On the other hand, if one is metastatic, then surgical resection would achieve survival of a T1 N0 M1 lesion.

Martini considered a second nodule to be synchronous if it was in situ, a different cell type and did not share the same lymph supply of the (presumably) distal nodule.(1) If these criteria were fufilled, the tumours could be considered as synchronous. There was a comment during the discussions that Martini made up these criteria, but if you think about it, they do make some sense.

The 6th revision of the UICC classification for lung cancer does not differentiate between synchronous and metastatic but considers a seperate nodule in the same lobe as T4 and in a different lobe as M1.(2) On conventional selection criteria patients with stage IIIB and IV are not considered for surgery.

I think all these arguments are flawed...

Continue reading "A tale of two nodules" »

Posted by Eric Lim at 02:57 PM | Permalink

Don’t be too amused by recent reports of a “small but significant” increase in thrombosis with drug eluting stents nor expect a windfall of patients queuing up, returning to the joyous cries of cardiac surgeons slapping themselves on the back singing “I told you so!”.

While monitoring for complications, the FDA states that it still currently “believes that coronary drug-eluting stents remain safe and effective when used for the FDA-approved indications”. Furthermore, the meta-analysis by Camenzind (presented to the 2006 European Society of Cardiology Annual Meeting) reported death and Q-wave MI increased in drug-eluting to bare-metal stents. The conclusions imply selective return to bare metal stents as opposed to a mass exodus towards coronary artery surgery.

As a group, we naturally extol what we like to hear and ignore what we don’t. Before peering over the fence at our neighbor’s gardens, maybe we should look at the results off pump graft patency. This month (December 2006) in the Journal of Thoracic and Cardiovascular Surgery, we reported a significant increase in graft occlusion in randomised trials of off pump compared to conventional surgery, but maybe you don’t really want to hear about that…

Posted by Eric Lim at 05:40 PM | Permalink

I read with some amusement an article by Gansera et al entitled “Does bilateral ITA grafting increase perioperative complications?: Outcome of 4462 patients with bilateral versus 4204 patients with single ITA bypass” in the August 2006 edition of the European Journal.

It was an article highlighted for CME, probably due to educational value and clinical importance, but certainly not on the quality of statistical reporting. It is surprising that an article of such standing reached the printing press with P=0.00 reported throughout the manuscript. It suggests that the authors and reviewers were unaware of the implications.

A P value is the probability of observing the given results or more extreme values given that there is no true difference (ie the “the null hypothesis is true”). Therefore P=0.00 means that the probability of observing the results or more extreme values is zero given that there is no true difference, which in itself is impossible. What the authors really meant was that the probability was less than 1% (ie P<0.01).

The tables in the manuscript were confusing, as they reported the percentages without actual numbers. Furthermore, the categories in some tables were subdivided by disease (eg 30-day mortality, table 7), therefore and the reported percentages had nothing to do with the denominators listed at the top of the table (BITA n=4462 and SITA n=4204).

The authors used multivariate instead of multivariable. A multivariable (correct term) analysis refers to one dependant variable and many explanatory variables, as per the standard logistic regression. A multivariate analysis means that there were more than one dependant variable that was analysed simultaneously, this is rarely used in medical literature, and consists of techniques such as principal component analysis and factor analysis.

Many other questionable aspects of the statistical reporting aside, I couldn’t help but feel that the article was reported in a manner biased towards BITA usage. The conclusion included:

“CABG using both ITAs can be performed routinely with good clinical results and low mortality. Compared with single ITA grafting, sternal and bleeding complications were slightly increased...”

which, after reading the paper I would rephrase as…

“CABG using both ITAs can be performed routinely (for perceived benefits from non-randomised observational studies that have usually performed BITA on selected healthier, lower risk patients) if you are willing to accept a longer duration of surgery, bypass time, cross clamp time, more bleeding, 4.8 fold increase in re-thoracotomy rate (why re-thoracotomy instead of re-sternotomy?), 2 fold increase sternal dehiscence and 3.5 fold increase in mediastinitis, with low mortality ”

Posted by Eric Lim at 12:19 AM | Permalink

Ok, maybe hate is too strong a word… I suppose I don’t really “hate” minimal access surgery, but rather the propaganda around a subject laced with soft secondary benefits whilst ignoring the primary aim for surgery.

Just because the access is smaller, it does not make what is done inside the body cavity less traumatic or invasive. If an equivalent procedure is performed, it will be as equally invasive. What saving is the “trauma” associated with a 4 inch versus an 8 inch sternotomy or the cumulative sum of 3 x 1.5 inch port sites versus a 8 inch limited thoracotomy, or a 6 inch limited thoracocomy and 2 x 1.5 inch port sites with VATS assistance versus 10 inch thoracotomy? If the procedure takes longer than conventional access surgery, would the duration of surgical trauma result in greater overall physiologic stress?

Many surgeons use the minimally invasive route as a self / institution promoting strategy hoping to gain more referrals and better patient acceptance for procedures where primary efficacy and safety are usually unconfirmed by randomised trials. Indeed, the primary aim is often forgotten in pursuit of surrogate marker to justify the performance of a possibly more expensive, less accessible, less complete and more compromising (during the initial learning curve) procedure. Why do most trials on VATS surgery for pneumothorax report pain and length of hospital stay instead of recurrence rates, and observation studies on minimal access revascularisation report pain and hospital stay instead of angiography graft patency, recurrence of angina and survival?

Reports of new techniques are often undertaken by enthusiasts in the field, who have a vested interested in proving what they are doing is better, and are often reviewers of papers related to these techniques, therefore how many papers critical to what they do would receive a good review?

My own views are that state of the art is not necessarily better, efficacy must be proven in the primary reasons for surgery before patients and referring physicians are “sold” the soft benefits of minimal access surgery.

Posted by Eric Lim at 01:38 PM | Permalink

Surely species are on the road to extinction when they are no longer able to adapt sufficiently to survive in a changing environment. But friends are important, and a good evolutionary deal is a symbiotic relationship, where two organisms can exist mutually reliant on each other for food. It’s much worse to be in a relationship like hyenas to lions where two animals feed on the same source but with the hyena relying on the lion for food.

Ok, so surgical revascularisation rates are down and percutaneous coronary intervention rates are on the rise, but don’t worry, there’s always aortic valve surgery, the second most commonly performed operation in cardiac surgery?

Hate to burst your bubble, but read it and weep, 50 percutaneous valve implants for aortic stenosis, regurgitation and failed prosthetic valves.

Ah ha! You may exclaim that the founder of CoreValve is a cardiac surgeon. He may have been involved in the development of the percutaneous valve! So, we will be able to participate in this new technology? Sure, all we need is for suitable patients to be referred for…. Oh! they already are experts in percutaneous interventions...

Posted by Eric Lim at 12:26 AM | Permalink

So, once again, Aprotinin is bad.

In the New England Journal of Medicine, the Perioperative Ischaemia Research Group just published the results of a large observational study encouraging readers not to use aprotinin after cardiac surgery. One of the main reasons cited in the paper was a doubling in the risk of renal dysfunction and renal failure.

The study is to be commended on the large sample size, an impressive 4374 patients in 69 institutions across the world. Whilst we, as readers and reviewers are often wary about conclusions based on small sample sizes concluding no difference when a true difference might exist, why don’t we display a similar scepticism about large studies that conclude a difference when none might exist?

Big is not always better, the authors state that in this setting, a randomised trial would be ideal but would be difficult “if not impossible” to conduct, and observational studies when sufficiently large may offer critical insights even in light of recognized limitations.

Unfortunately they are missing the point. A small randomised trial will give you an estimate that is closer to the truth, because baseline differences are balanced, but the results may be imprecise (wide confidence interval) that is progressively narrowed by increasing the sample size.

However, a large observational study may give you a very precise estimate, but it may be far from the truth (influenced by bias arising from differences in the groups compared), that can never be corrected by increasing the sample size.

Precision of the estimate is never more important than a correct estimate!

Continue reading "Aprotinin: propensity for confusion" »

Posted by Eric Lim at 08:28 AM | Permalink

There is a great article by Professor David Taggart , also mentioned by Professor Tom Treasure, about the current interpretation of clinical trials comparing PCI (mainly stenting) against CABG. One of the main premises is that cardiologists are not providing the standard of care of revascularization, stemming from (or is justified by) revascularization trials that include a significant proportion of patients with coronary disease distribution that are known not to derive survival benefit with CABG.

Whilst I would love nothing more than to support any cause that would lead to more work for the specialty, I think there is more to the debate.

Wouldn’t it be really unethical to randomize patients with coronary disease anatomy that are already known to derive a survival benefit from CABG to receive PCI? Also, there is no onus to prove that CABG is superior. As far as I can see, the PCI trials ask a different question: `in patients who are amenable to both form of treatment, is there any difference in the outcome between PCI and CABG?’. The trials mainly have the same message, which is lower re-intervention with CABG and no difference in survival. An interesting exception is the SOS trial, where survival was statistically significantly improved with CABG, but the result was glossed over by the reporting authors ("The apparent reduction in mortality with CABG requires further investigation").

We will never stand a fair chance in any revascularization war.

Continue reading "Revascularization wars" »

Posted by Eric Lim at 05:09 PM | Permalink

I reviewed a manuscript recently. Researchers were reporting a new test to diagnose `Christmas pudding embolism’ (details altered to preserve confidentiality).

Using a `mistletoe test’ (well, the baseline investigation they chose was not that well known either!) you achieved a sensitivity of 15% (95% CI 10 to 23%), and the new `red-nose reindeer’ test achieved a sensitivity of 49% (95% CI 45 to 55%). They concluded that the `red-nose reindeer’ test was at least 3 times more sensitive and should considered for routine diagnosis of `Christmas pudding embolism’.

Problem? Yes… a misconception that invalidates their conclusion.

Continue reading "Sensitive issues" »

Posted by Eric Lim at 09:41 AM | Permalink

I love being in an era where new technology is being evaluated. I sat in a lecture by a famous liver surgeon (Alan Johnson) in Sheffield (UK, where they filmed the `Full Monty’) prior to his retirement. He said that he had seen it all with regards to surgical research. It always follows the same pattern. First everyone loves a new surgical advancement, then everyone hates it, then we find indications for its appropriate use.

I think off-pump surgery is between phase 1 and 2 of the `Johnson chronology’. What really amuses me is how evangelical surgeons can be when defending their preferred technique. The sentiments are best reflected in this great quote:

`To cut things short, it is extremely important to understand that there is abundant clinically relevant though not necessarily statistically significant, scientific evidence to validate the midterm safety and efficacy of OPCAB.’ Anesthesiology 2005; 103: 902.

Frankly, surgical research can never be 100% replicable and reporting can never be 100% free from bias. The variances in patient response to a tablet (due to pharmacokinetics, pharmacodynamics differences) are usually balanced out if a trial is large enough, but no two surgeons will operate with the same skill. A new procedure that is shown to be superior compared to the standard in the hands of gifted surgeon A, may be inferior to the standard in two-left-hands surgeon B.

Continue reading "Off-pump or off handed?" »

Posted by Eric Lim at 02:42 PM | Permalink

Statistics, I never understood any of it, but strangely the formidable aura generated by the knowledge and interpretation of the numbers gave an authority to textbooks and anyone who possess knowledge of it (a bit like Frodo in Lord of the rings).

Cardiothoracic surgery must be the single specialty where the use of statistics is most advanced. Just open any page in Kirklin's and you will be accosted by the most impressive series of numbers, equations and diagrams. Have you ever seen a comparable book in any other medical specialty? To be honest, I’ve always thought that you need a Masters in Statistics to fully comprehend it. It’s exactly what I obtained, and today I think it’s truer than ever.

What hope is there for the standard reader to understand the masses of information presented? The disability leads to a major vulnerability - when you cannot interpret the raw data, you become critically reliant other peoples interpretations.

Continue reading "Surgery, statistics, subjective interpretations, seniority and staying out of trouble" »

Posted by Eric Lim at 10:13 PM | Permalink