Two disconcerting papers

We all know that mutations cause cancer and that MRI lesions cause disability in multiple sclerosis. We do, don’t we? Maybe we don’t, say two papers out this October.

First: cancer. The number of mutations in stem cells from 3 organs (liver, colon, small intestine) was determined in biopsy samples from 19 people ranging in age 3 to 87 [ Nature vol. 538 pp. 260 – 264 ’16 ].th How did they get stem cells? An in vitro system was sued to expand single stem cells into epithelial organoids, and then the whole genome was sequenced of each. Some 45 organoids were used. Some 79,790 heterozygous clonal mutations were found. They then plotted the number of mutations vs. the age of the patient. When you have a spread in patient ages (which they did) you can calculate a tissue mutation rate for its stem cells. What is remarkable, is that all 3 tissues had the same mutation rate — about 40 mutations per year. Not bad. That’s only 4,000 if you live to 100 in your 3.2 BILLION nucleotide genome.

This is so  remarkable because the incidence of cancer is wildly different in the 3 tissues, so if mutations occurring randomly cause cancer, all 3 tissues should have the same cancer incidence (and there is much less liver cancer than gut cancer).

Of course there’s a hooker. The numbers are quite small, only 9 organoids from liver with a relatively small age range spanning only 25 years. There were more organoids from colon and small and the age ranges was wider but, clearly, the work needs o be replicated with a lot more samples. However, a look at figure one shows that the slope of the plot of mutation number vs. age is quite similar.

Second: Multiple sclerosis. First, some ancient history. I started in neurology before there were CAT scans and MRIs. All we had to evaluate the MS patient was the neurologic exam. So we’d see if new neurologic signs had developed, or the old ones worsened. There were all sorts of clinical staging scores and indices. Not terribly objective, but at least they measured function which is what physician and patient cared about the most.

The MRI revolutionized both diagnosis and our understanding of MS. We quickly found that even when the exam remained constant, that new lesions appeared and disappeared on the MRI totally silent to both patient and physician. I used to say that prior to MRI neurologists managed patients the way a hematologist would manage leukemics without blood counts, by looking at them to see how pale they were.

In general the more lesions that remained fixed, the worse shape the patient was in. So new drugs against MS could easily be evaluated without waiting years for the clinical exam to change, if a given drug just stopped lesions from appearing — stability was assumed to ensue (or at least it was when I retired almost exactly 4 presidential elections ago).

Enter Laquinimod [ Proc. Natl. Acad. Sci. vol. 113 pp. E6145 – E6152 ’16 ] which has a much greater beneficial effect on disability progression (e.g. less) than it does on clinical relapse rate (also less) and lesion appearance rate on MRI (also less). So again there is a dissociation between the MRI findings and the patient’s clinical status. Here are references to relevant papers — which I’ve not read —
Comi G, et al.; ALLEGRO Study Group (2012) Placebo-controlled trial of oral laquini- mod for multiple sclerosis. N Engl J Med 366(11):1000–1009.

Filippi M, et al.; ALLEGRO Study Group (2014) Placebo-controlled trial of oral laqui- nimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry 85(8):851–858.

Vollmer TL, et al.; BRAVO Study Group (2014) A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol 261(4):773–783.

It is well known that there are different kinds of lesions in MS (some destroying axons, others just stripping off their myelin). Since I’ve left the field, I don’t know if MRI can distinguish the two types, and whether this was looked at.

The disconcerting thing about this paper, is that we may have given up on drugs which would  clinically help patients (rather than a biological marker) because they didn’t help the MRI ! ! !

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