Saturday, May 19, 2018

Liquid Biopsies Again

A recent ASCO/CAP panel reported on the current status of liquid biopsies and use of ctDNA. We have recently examined this area and although of some interest it is not yet clinically acceptable. In OncLive they report on the Panel. They note:

ctDNA assays is challenging because of the lack of prospective trial data compared with available research on standard biopsies for tumor genotyping. At present, just the cobas EGFR Mutation Test v2 for non–small cell lung cancer (NSCLC) has demonstrated sufficient clinical utility to gain FDA approval. Polymerase chain reaction–based ctDNA assays for EGFR in NSCLC and KRAS in colorectal cancer are available for commercial use in Europe, but— as was the case for cobas—their clinical utility was established using retrospective analysis. There is limited evidence of clinical validity of ctDNA analysis in other tumor types and for variants that were not analyzed as part of the ctDNA studies for EGFR in lung cancer and KRAS in colorectal cancer. A wide range of ctDNA assays have been developed and clinically studied for detection of potentially targetable variants, such as BRAF variants in melanoma and PIK3CA and ESR1 variants in breast cancer. Although several liquid biopsy tests are commercially available, their clinical utility has not been established.

The ASCO report states:

1. There is not enough evidence, at this time, to know whether use of the majority of ctDNA tests in
advanced cancer is justified, outside of screening for participation in, or during, a clinical trial.
2. There is not enough evidence, at this time, to support the routine use of ctDNA tests for early-stage
cancer, making treatment decisions, monitoring how well a treatment is working, finding remaining
cancer cells, or for cancer screening, except screening for participation in, or during, a clinical trial.
3. There are inconsistent findings when testing with liquid biopsies versus testing with tumor tissue, so negative liquid biopsy results should be confirmed with tumor tissue genotyping. 

The ASCO paper notes:

Evidence on the Use of ctDNA Assays for Treatment: Selection in Advanced Cancer The clinical validity of ctDNA assays has been the subject of multiple studies in select cancer types. In general, PCR-based assays for detection of oncogenic driver variants have very high diagnostic specificity, but more modest diagnostic sensitivity. For example, in lung cancer, in a review of five studies that used tissue genotype as the reference standard, specificities for canonical driver variants averaged 96% (95% CI, 83% to 99%), and sensitivities averaged 66% (95% CI, 63% to 69%). For variants selected before treatment, such as the EGFR T790M variant in the setting of acquired resistance, sensitivities remained moderate, whereas specificities showed more variability (range, 40% to 78%), a difference believed to be a result of the genomic heterogeneity of treatment resistance. PCR-based ctDNA assays for KRAS genotyping in colorectal cancer have also been systematically analyzed and demonstrate high specificity and moderate sensitivity. Fundamentally, there are two paradigms to demonstrate clinical utility and the adoption of ctDNA as a clinically useful test. The most reliable are prospective clinical trials to test the clinical utility of ctDNA as a stand-alone diagnostic test. No such trial has been reported to date. A second strategy is to assess whether ctDNA provides the same information as tissue genomic evaluation.

Overall there may be some conceptual utility and it is an area worth further study but the efficacy and utility is open to question as we had noted.


Merker et al, Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review, March 2018,

Friday, May 18, 2018

The EHR, Legacy of Obamacare

Ten years ago we argued against the way the EHR was being developed. Some idealistic left wing academic took control and had designed the rules under which this system now works. What did we say then and what is true now"

1. Patient's Records should be the Patient's Records. Instead they are the provider's records and as such when you go from one provider to another the records are inaccessible. Google and Microsoft took a swing at it but looking back who trusts them?

2. Physicians are NOT Clerks: This means that we do not want the physician spending hours entering records and finding ways to make it easier but less effective. We now have EHR staff adding to costs which are one of the reasons for increasing Health Care expenses.

3. AI cannot replace a physician. Despite Watson and all that hype there must be a human to human interface. Try placing a call to customer service anywhere, you spend a half hour with some moronic speech recognition device and usually end up at the wrong place multiple times. Patients lie, the tell you they do not drink, much, do not smoke, at least before coming to your office, do not use drugs, except for those they got from their sister.

The list can go on. In today's NY Times an author notes:

The biggest price for “digital medicine” is being paid by physicians like the sad case seated before me, who is already considering jumping to venture capital or a start-up, not because that is where the heart is but because it’s a place to bail out to. By some estimates, more than 50 percent of physicians in the United States have at least one symptom of burnout, defined as a syndrome of emotional exhaustion, cynicism and decreased efficacy at work. It is on the increase, up by 9 percent from 2011 to 2014 in one national study. This is clearly not an individual problem but a systemic one, a 4,000-key-clicks-a-day problem. The E.H.R. is only part of the issue: Other factors include rapid patient turnover, decreased autonomy, merging hospital systems, an aging population, the increasing medical complexity of patients. Even if the E.H.R. is not the sole cause of what ails us, believe me, it has become the symbol of burnout.

Every patient is different, most are terrified that they are dying, on the spot or soon. Many have neglected the problem that has now morphed into something more serious. The Times also showed hod US life-expectancy had lagged behind other countries. A physician today can tell you why by just looking at their waiting room. A collection of obese humans refusing to change. But how does that get to an AI system of to an EHR.

As Osler said, paraphrasing, "If all else fails listen to the patient." In today's EHR world it should read: "If all else fails look at the patient."

Monday, May 14, 2018

A Monster of Our Own Making?

The smartphone is a creature which seems to be gaining its own life. Now I must admit I have no smartphone, and I really do not want one. Permit me to explain why. First, as some may know, I had been the COO of what is now Verizon Wireless and as such established the current digital network along with Qualcomm. Prior to that, as a matter of happenstance I inherited the first international connections of the ARPA Net, now the Internet between Etam WV and Goonhilly in the UK and Trondheim in Norway. Of course I also was responsible for expanding broadband Internet to Central and Eastern Europe. However I had nothing to do with the smartphone, kind of.

But back to the smartphone. As I see it as one not infected by them, it is a device which is taking over part of humanity. It tells people what to think, what to do, when to do it. It monitors your health, your heart rate, blood pressure, blood sugar, and can listen to you 24 by 7, tracks your location, and can tell you where to go next, what to do there, what to say, how long to stay etc. It can tell you who to date, who to speak with. You are not in control, the smartphone and its manipulators are. And these smartphone are all interconnected, one massive and expanding distributed computer, sharing information on all the humans they are controlling. You keep the phones charged, buy new and faster ones, interconnect them on clouds, and follow their every command.

Smart phones now monitor where you are and then "suggest" what you should do next. Smartphones tell you who to date. Smartphone tell you when to exercise, what to eat, and when you must lose weight. Smartphones tell you what news to read, how to view your politicians, they anticipate your next move and then before you get there tell you what is "best" for you. Smartphones give you lists, the lists of books, movies, restaurants, you may be thinking you have the choice but the smartphone already knows how you will choose from the list they give you.

Smartphones can assemble a crowd, create a mob, just by sending messages to targeted individuals. The smartphones know your hot buttons, they have trained you, and you have gladly participated. Smartphones talk to your smartcar, your driverless smartcar. The smartcar takes direction from the smartphone and not from you, even though you think it is.

In effect, the smartphones are using you to effect what they are not yet able to do. But when the robots get a bit better the smartphones may never need you again, and then what. The smartphones have learned all they need to from you, you have become obsolete. They now control the factories, the robots, the transportation systems.

Can smartphone even go to war with one another? Is that programmed in as well. Can they talk to a nuclear missile?

Thus the problem is not Facebook, Google, it is the smartphone. It is a diabolical device that is sucking out what is left of the intellect of humans and learning how to control them. Learning how to make them obsolete.

Frankenstein was not a composite of dead humans, it is not a carbon based monster, it is a silicon based monster.

Friday, May 11, 2018

PSA Testing: An Interpretation

After yesterday's commentary and the "looking" at it by the folks in DC I felt it would be worth a simple graph, simple at least for me. Here goes:

The above is a simple analysis.

1. Assume two types of PCa exponential growth rates, a fast and a slow. The growth rates are 0.30 and 0.15 cells per month and the horizontal axis is months.

2. Also assume that at 1 million cells we can just start to detect a malignancy, say PSA rise and at 1 billion cells our poor guy is dead. These are used by Weinberg so they are reasonable.

3. We show the cell numbers and the two levels.

4, In about five years our aggressive type kills the patient. The slower type takes almost 12 years. In reality there may be multiple types which never kill a patient. But this is just an example.

5. Now assume we do PSA tests every 2 years, even more frequent than some of the "gold" standard studies, but worth a look.

6. From our model we may just detect a PSA change in the aggressive type at year 4 and we say don't worry, come back in 2 years. He never gets to come back, he is dead two months before his next test!

7. The slower growth may afford time under this protocol.

8. If we had tests every six months for this patient we most likely could have saved him.

This is the point I have been making. Namely in order to really do this study properly you need to separate types of PCa into pools and then do the analysis. To separate you must do much more frequent testing otherwise the poor fellow with the aggressive type will die and you will just consider the use of a PSA test as futile. The true answer is your testing methodology is futile.

Thursday, May 10, 2018

They are at it Again!

The USPSTF is issuing a new and updated recommendation. The "new" recommendation is:

The USPSTF concludes with moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small for some men. How each man weighs specific benefits and harms will determine whether the overall net benefit is small. The USPSTF concludes with moderate certainty that the potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harms.

Now read this carefully. "for some men" really means that we still have no idea how to identify the deadly form of PCa. So if a man has "harms" he should consider "death" as an alternative?

They note the harms of the test:

The harms of screening for prostate cancer include harms from the PSA screening test and subsequent harms from diagnosis and treatment. Potential harms of screening include frequent false-positive results and psychological harms. One major trial in men screened every 2 to 4 years concluded that, over 10 years, more than 15% of men experienced at least 1 false-positive test result. Harms of diagnostic procedures include complications of prostate biopsy, such as pain, hematospermia (blood in semen or ejaculate), and infection. Approximately 1% of prostate biopsies result in complications requiring hospitalization. The false-positive and complication rates from biopsy are higher in older men. Adequate evidence suggests that the harms of screening and diagnostic procedures are at least small.

Generally a competent urologist can perform a biopsy, especially is MRI/US guided with 20+ cores in a manner to have a high sensitivity and specificity and do so with limited discomfort and if prep is proper then the chance of infection can also be minimized. The problem remains on determining the aggressiveness of the lesion. Even a 3+4 Gleason may genetically become aggressive.

I would argue that the data they use is still problematic at best. Proper PSA testing requires a long term annual at least measurement with percent free. From that one can obtain velocity which is essential. Also family history is essential. Then using Bayesian methods one can reasonably approach the patient. The literature referenced was not where close to such a protocol, testing was spotty at best as we have noted before. The results from a decade ago as we had demonstrated reflected in our opinion a fatally flawed test. The measurements were no annual at the very least, and as one delays testing an aggressive form may take over and eliminate any advantage.

 There needs to be a good clinical study where PSA is measured on a more frequent basis. The problem we face is that PCa can be genetically diverse and at one extreme, the dominant one, we have a relatively indolent disease. At the other extreme, we have a very aggressive type, which progresses very quickly. In doing any statistical analysis one must examine the results from both sets separately and thus one must perform more frequent PSA especially on this subgroup. In my opinion that is the basis of a fatal flaw.

Wednesday, May 9, 2018

Individualism vs Progressives

The Libertarians at George Mason often take the extreme positions on may things but this time they are spot on regarding the Progressive mind set. As noted in Cafe Hayek:

Does Mr. Trone really believe that politicians and government officials in Washington care more about each of the millions of individuals and families throughout the United States than does each individual about himself or herself and his or her family? Does Mr. Trone think that distant rulers and mandarins know more about each individual’s and family’s circumstances and dreams than does each individual? Does Mr. Trone suppose that a society of individuals and families relieved of the personal responsibility of making the appropriate investments in their lives – and shielded from the need to confront life’s trade-offs – will eventually be anything but a society of citizens and voters who are incurably irresponsible? And does Mr. Trone deny that government, to the extent that it assumes more of the responsibility of “investing in” individuals and families (and, hence, individuals and families assume less such responsibility), will inevitably insist on greater control of the life’s choices of individuals and families – life’s choices ranging from the mundane to the intimate?

Frankly I believe it is worse than what Boudreaux states. The believer in Individualism believes that all individuals have equal rights before the law and they should not be discriminated against in any fashion and that performance of the individual is what counts. The Progressives believe that a small group know better than the rest of us and that the group should come up with a plan for our lives. 

Whether it is control of speech, control of expression, control of employment, and so forth, the Progressive firmly believe they have been given the truth and they seek to enforce it. Pity.