General Petraeus has Prostate Cancer

[Guest]

Another interesting point was that for every cancer identified, 1400 screenings would need to be done. Well, what's the big deal here? A DRE and a PSA are hardly strenuous exercises.

 

 

Let's face it, if you were offered the choice of say, not being able to produce ejaculate at the age of 60 or over, or dying prematurely from prostate cancer, which would you choose?

I'm glad you had about as good a result as one can expect. Actually, many cancers were identified (much more than 1 per 1400 screened), although I think the statistic was that it took 1400 screened for one life to be extended by prostate cancer screening (although more than 1/1400 died due to the screening). In a court of law, the winner is determined by who puts up the best argument. In medicine, we hope to make decisions based on facts rather than who argues the best. The problem is that while DRE and PSA are not difficult or dangerous tests in and of themselves, what follows when one is abnormal (as they very often are) does become "strenuous" and dangerous. So far there hasn't been a single study which has shown that screening prevents premature death, and no one can argue that point. Since the studies have been very large, even clinically insignificant (but statistically significant) differences would be found had they been present.

I just saw an elderly (82 yo) gentleman today whose life was ruined by prostate cancer screening in 1992. He ended up getting scarred ureters, and having to have a new bladder made out of intestines, requiring a tube be places through his stomach, with monthly catheter changes, frequent infections, etc. His penis has served no function in 17 years. Interestingly, despite surgery AND radiation, they never got all of the cancer out, and here he is 17 years later, certainly none the better for all of the surgery and radiation. Although there has been hormonal treatment, the cancer never spread to the bone or anywhere else important.

While the studies are continuing and could conceivably show benefit at over 15 years, given our current state of knowledge, it's very important for anyone contemplating prostate cancer screening to know the facts, and not just the rhetoric.

[Luv2play]

(although more than 1/1400 died due to the screening). In a court of law, the winner is determined by who puts up the best argument. So far there hasn't been a single study which has shown that screening prevents premature death, and no one can argue that point. I just saw an elderly (82 yo) gentleman today whose life was ruined by prostate cancer screening in 1992. and here he is 17 years later, certainly none the better for all of the surgery and radiation. Although there has been hormonal treatment, the cancer never spread to the bone or anywhere else important.

.

 

When you say more than 1/1400 died due to screening, do you not mean they died "despite" screening? By drawing a causal link, you are saying the screening led directly to their deaths. How could this be? Did they die on the operating table because of botched surgery?

 

The European study showed that there were significantly fewer deaths in the screened group of a very large sample of men between 55 and 69. Can't we conclude there were fewer premature deaths?

 

In the case of the 82 year old, while he suffered horrible side effects, the fact remains that there have been huge advances in the surgical techniques made since 1992 when he had his initial operation. As in many branches of medicine, patients receiving treatment today often face far better outcomes than just a few years ago because of technological breakthroughs and similar advances.

 

In addition, who is to say that this patient wouldn't be dead by now if he hadn't had the treatment to take out the cancerous tumours. The cancer may have spread more extensively in the absence of treatment.

 

In any event, I see that the American Cancer Society is going to fine-tune their messages on breast and prostate cancer screening because of recent studies. It will be interesting to see what they arrive at.A good debate is always helpful in re-examining views and maybe changing certain practices.

[Guest]

When you say more than 1/1400 died due to screening, do you not mean they died "despite" screening? By drawing a causal link, you are saying the screening led directly to their deaths. How could this be? Did they die on the operating table because of botched surgery?

 

It was just an observation. I tiny amount more of the screened population died. I doubt that the major cause was literally death on the operating table. More likely, it was due to secondary effects. These can be extraordinarily numerous, including infections, possibly blood clots/pulmonary embolism after the surgery, bleeding complications, suicide, effects of hormonal treatment or radiation--the list can go on and on. This is why one cannot apply "logic" to medical decisions. Even case-control studies can lead to false conclusions. In the 90s, there was strong evidence from case control studies which showed that women who took estrogen after menopause lived longer, had fewer heart attacks and strokes, and so on. It took a randomized clinical trial to see that this was not the case (at least for the time period studied, of a few years, in the women studied, mainly women in their 60s).

The list of myths debunked by RCT's is huge. Antioxidants such as Vitamins A, C ,and E didn't prevent any illness (actually associated with a slightly higher morbidity rate). People who took echinacia actually had their colds last 5 hours longer than those who took placebos (not significantly longer, but certainly not better). Basic science, epidemiology, and even case control studies provide food for thought, but reality only can become apparent with RCTs when dealing with a complex system such as the human body.

[Guest greatness]

Dr. Brawley's Editorial

 

I hope this article helps some people to understand why some physicians are cautious about PSA screening. It is a complicated topic.

 

 

J

 

EDITORIALS

 

Prostate Cancer Screening; Is This a Teachable Moment?

 

Otis W. Brawley

Affiliations of author : American Cancer Society, Altanta, GA; Departments of Hematology and Oncology, Department of Medicine, and Department of Epidemiology, Emory University, Altanta, GA

 

Correspondence to: Otis W. Brawley, MD, American Cancer Society, 250 Williams St, Suite 600, Atlanta, GA 30303 (e-mail: [email protected]).

 

In this issue of the Journal, Welch and Albertsen (1) presented information that every man considering prostate cancer screening and treatment should know and understand. Prostate cancer screening has resulted in substantial overdiagnosis and in unnecessary treatment. It may have saved relatively few lives. Results from this article and recent results from prostate cancer screening and prevention trials demand reflection about what we as a society have done and are doing. Lessons to be learned have ethical and economic implications and involve our lack of respect for the scientific process and scientific evidence.

 

As I sat down to write this editorial, I heard a radio commercial that brings perspective to the issue. A local celebrity was promoting prostate cancer awareness. He said, "Prostate cancer is 100% curable when caught early." He encouraged all men to get screened and announced that a van was touring the area offering screening in supermarket parking lots. This was a community service project sponsored by the radio station, the supermarket chain, and a radiation oncology practice.

 

A commercial like this plays to our fears and prejudices. All of us have been taught from an early age that the best way to deal with cancer is to find it early. With the development of the prostate-specific antigen test, prostate cancer screening and early detection efforts surged in the United States in the late 1980s and continue to this day (2,3). By 1991, there were large prostate cancer awareness campaigns, health systems, and others who stood to profit from prostate cancer screening and treatment and encouraged it, implying benefit to those screened (4). Many were eager to push screening because of a financial incentive; some simply did not think too deeply due to the financial gain. Others truly thought they were doing a public service and felt urgency because prostate cancer is a leading cause of cancer death.

 

Although there was clear evidence of early detection, there was little evidence to show that screening decreased prostate cancer mortality or saved lives. There was strong vocal "expert opinion" that surrogate endpoints of earlier stage at diagnosis and increased survival indicated that screening saved lives. Some experts expressed legitimate concern that screening was unproven and premature (5). Collins and Barry (6) noted that screening advocates were using the same mistaken arguments that caused the advocacy of lung cancer screening with chest X-ray in the 1960s. This intervention was abandoned in the 1970s after trials showed it ineffective.

 

Many screening advocates (both physician and lay) have had difficulty accepting that some cancers are not going to progress and cause symptoms or death within the lifetime of the patient (7). The distinguished urologist Willet Whitmore recognized overdiagnosis as a problem in his famous quote, "The quandary in prostate cancer: Is cure necessary in those for whom it is possible, and is cure possible in those for whom it is necessary?"(8)

 

Truth be known, most of our pathological definitions of cancer were developed in the mid-1800s using light microscopy (9). Prostate cancer has not moved fully into the molecular and genetic age (10). We desperately need the ability to predict which patient has a localized cancer that is going to metastasize and cause suffering and death and which patient has a cancer that is destined to stay in the patient's prostate for the remainder of his life.

 

Because of overdiagnosis, the true effect of prostate cancer screening cannot be assessed by the increased proportion of low-stage tumors at diagnosis. Overdiagnosis also artificially prolongs survival statistics meaning survival statistics cannot be used to determine a positive screening effect. Indeed, the only trusted measure of screening success can be decreased cause-specific mortality as seen in a randomized clinical trial (7).

 

Lesson 1: Have respect for science and the scientific process. Understand and address the truly important questions.

 

"Does prostate cancer screening save lives?" is still a legitimate question. A recently published analysis of an American prospective randomized trial (11) showed no benefit to screening with up to 10 years of follow-up. A European study (12) showed a 20% decline in mortality after 9 years of follow-up with substantial overdiagnosis. More than 1400 men have to be screened and 48 additional men diagnosed and treated to avert one prostate cancer death after 9 years.

 

There has been a 40% decline in US prostate cancer mortality since 1993. The reasons are not known. It could be because of screening, more effective treatment of metastatic disease, changes in attribution of cause of death, or other factors (13). The American screening trial (hindered by our prejudice for screening) would suggest that screening attributed nothing to the statistic. The European study would estimate screening caused about half of the decline. It is of note that countries that do not have widespread screening as a policy have seen some declines in prostate mortality without the harm of frequent overdiagnosis (14).

 

The early detection prejudice delegitimized the questions concerning screening and what are now clearly important scientific questions concerning disease prognostic factors and predictors of biological behavior. Indeed, over the past 20 years, many research dollars were spent addressing the question "how can men be encouraged to get screened?" when projects to better understand prostate cancer biology were not funded.

 

After we determine who needs treatment and who does not, we need to know how good the treatments are. Today there are nearly a dozen treatments for localized prostate cancer. Some of these treatments are very expensive and some have serious and long-lasting side effects (15,16). Little has been done to figure out which therapies are most effective. Every treatment looks good, when more than 90% of men getting it do not need it.

 

Lesson 2: In the past we have truly not appreciated the need for scientific evidence. In the future, will we accept scientific evidence?

 

Prostate cancer screening is not the only intervention we have adopted prematurely. Medicine and especially American medicine has often relied on the opinion of experts (often biased experts) rather than on the objective interpretation of scientific data. Too often, we have allowed opinion to undermine support for scientific study. Indeed, the list of medical interventions adopted and later withdrawn or substantially modified after initial assessment was determined incomplete is long. Among them are 1) the Halsted mastectomy for breast cancer (17), 2) bone barrow transplant for high-risk breast cancer (18), 3) neuroblastoma screening with a urine test (18,19), 4) lung cancer screening with chest X-ray (20), 5) erythropoetin therapy during chemotherapy (21), and 6) postmenopausal hormone replacement therapy (22).

 

The current political rhetoric supports "comparative effectiveness research." In principle, this is good. The strongest scientific supports for an intervention are findings from a prospective randomized controlled trial. In the case of prostate cancer screening, many screening advocates actually discouraged such trials even while the trials were under way.

 

Unfortunately, prospective randomized trials are not always practical because of expense or the needed duration. Some clinical decisions do need to be made through interpretation of results of lesser studies. These results need to be interpreted carefully and with an open mind. At times, the opinions of respected authorities based on clinical experience will need to be used. These authorities must remain objective.

 

Lesson 3: The rational use of medicine, not the rationing of medicine.

 

An important element of health-care reform is a reform of how we consume health care. The irrational tendency to adopt treatments and technologies without adequate assessment is a form of "medical gluttony" and a major reason that US per capita health-care costs are the highest in the world. We do not get what we pay for; our life expectancy is 29th among developed countries. Medical costs are approaching one-fifth of our gross domestic product (23). The economy cannot afford the continued growth of health-care costs seen over the past 30 years. Economic realities have already led to some restrictions or rationing. More will occur unless we begin the rational practice of medicine.

 

Lesson 4: Know what is known, know what is not known, and know what is believed. Label them accordingly.

 

The most important lesson of the prostate cancer screening saga is that we should appreciate the truth and clearly explain it as best as possible. Many men who thought their lives were saved by being screened, diagnosed, and treated for localized prostate cancer are perplexed to learn that so few benefit. They may be even more amazed that this is not a new finding. What is new is the fact that many health professionals are finally accepting it as true. They are accepting that there is overdiagnosis, unnecessary treatment and overtreatment, and questions regarding screening for this disease. They do this after several studies using varying methodologies have clearly shown that prostate cancer screening and treatment are very complicated (24–29).

[Guest greatness]

Dr. Brawley's Editorial Part 2

 

Journal of the National Cancer Institute [0027-8874] Brawley yr:2009 vol:101 iss:19 pg:1295 -1297

 

I come from and have been supported by an African American community, where many are suspicious of physician motives and are convinced that doctors and those in medicine will take advantage of them and not tell them the truth. Distrust is actually a major reason for many disparities in health faced by black Americans (30). A closed-minded medical culture is a part of the problem. The well-meaning uninformed layman with a sound bite is also a part of the problem. Both can cause serious harm.

 

Given the estimates of Welch and Albertsen and the results of screening (11,12) and prevention (31) trials, we now know that prostate cancer is a highly complicated disease and prostate cancer screening is a complicated intervention. The benefits of prostate cancer screening are still open to question. This means that informed or shared decision making should be done using the data now available before screening is performed. Some of the confusion of prostate cancer screening can be avoided if we all clearly label what we know, as what we know; what we do not know, as what we do not know; and what we believe, as what we believe. Of course, one must not confuse what is believed with what is known to do this.

 

 

NOTES

 

No conflicts of interest.

 

REFERENCES

 

1. Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after introduction of prostate-specific antigen screening: 1986–2005. J Natl Cancer Inst (2009) doi: 10.1093/jnci/djp278.

2. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. In: CA Cancer J Clin. 59(1):27–41.

3. Boyle P, Brawley OW. Prostate cancer: current evidence weighs against population screening. CA Cancer J Clin (2009) 59(4):220–224.[Free Full Text]

4. DeAntoni E, Crawford ED, Stone NN, et al. Prostate Cancer Awareness Week, 1992: a summary of key findings. Clin Invest Med (1993) 16(6):448–557.[Web of Science][Medline]

5. Garnick MB. Prostate cancer: screening, diagnosis, and management. Ann Intern Med (1993) 118(10):804–818.[Abstract/Free Full Text]

6. Collins MM, Barry MJ. Controversies in prostate cancer screening. Analogies to the early lung cancer screening debate. JAMA (1996) 276(24):1976–1979.[Abstract/Free Full Text]

7. Kramer BS, Brown ML, Prorok PC, Potosky AL, Gohagan JK. Prostate cancer screening: what we know and what we need to know. Ann Intern Med (1993) 119(9):914–923.[Abstract/Free Full Text]

8. Montie JE, Smith JA. Whitmoreisms: memorable quotes from Willet F. Whitmore, Jr, M.D. Urology (2004) 63(1):207–209.[CrossRef][Web of Science][Medline]

9. Gardner WA Jr. Histologic grading of prostate cancer: a retrospective and prospective overview. Prostate (1982) 3(6):555–561.[CrossRef][Web of Science][Medline]

10. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA (1998) 280(11):975–980.[Abstract/Free Full Text]

11. Andriole GL, Crawford ED, Grubb RL III, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med (2009) 360(13):1310–1319.[Abstract/Free Full Text]

12. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med (2009) 360(13):1320–1328.[Abstract/Free Full Text]

13. Lu-Yao G, Stukel TA, Yao SL. Changing patterns in competing causes of death in men with prostate cancer: a population based study. J Urol (2004) 171(6, pt 1):2285–2290.[CrossRef][Web of Science][Medline]

14. Shibata A, Whittemore AS. Re: prostate cancer incidence and mortality in the United States and the United Kingdom. J Natl Cancer Inst (2001) 93(14):1109–1110.[Free Full Text]

15. Lu-Yao G, Moore DF, Oleynick JU, DiPaola RS, Yao SL. Population based study of hormonal therapy and survival in men with metastatic prostate cancer. J Urol (2007) 177(2):535–539.[CrossRef][Web of Science][Medline]

16. Fowler FJ Jr, Barry MJ, Lu-Yao G, Roman A, Wasson J, Wennberg JE. Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988-1990 (updated June 1993). Urology (1993) 42(6):622–629.[CrossRef][Web of Science][Medline]

17. Veronesi U, Saccozzi R, Del Vecchio M. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med (1981) 305(1):6–11.[Abstract]

18. Lake DE, Hudis CA. High-dose chemotherapy in breast cancer. Drugs (2004) 64(17):1851–1860.[CrossRef][Web of Science][Medline]

19. Maris JM, Woods WG. Screening for neuroblastoma: a resurrected idea? Lancet (2008) 371(9619):1142–1143.[CrossRef][Web of Science][Medline]

20. Marcus PM, Bergstralh EJ, Fagerstrom RM, et al. Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst (2000) 92(16):1308–1316.[Abstract/Free Full Text]

21. Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst (2005) 97(7):489–498.[Abstract/Free Full Text]

22. Warren MP. A comparative review of the risks and benefits of hormone replacement therapy regimens. Am J Obstet Gynecol (2004) 190(4):1141–1167.[CrossRef][Web of Science][Medline]

23. The CIA World Factbook (2009) Washington, DC: US Government Printing Office.

24. Brawley OW. Prostate carcinoma incidence and patient mortality: the effects of screening and early detection. Cancer (1997) 80(9):1857–1863.[CrossRef][Web of Science][Medline]

25. Lu-Yao G, Albertsen PC, Stanford JL, Stukel TA, Walker-Corkery E, BarryScreening, treatment MJ. prostate cancer mortality in the Seattle area and Connecticut: fifteen-year follow-up. J Gen Intern Med (2008) 23(11):1809–1814.[CrossRef][Web of Science][Medline]

26. Lu-Yao G, Albertsen PC, Stanford JL, Stukel TA, Walker-Corkery ES, Barry MJ. Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut. BMJ (2002) 325(7367):740.[Abstract/Free Full Text]

27. Albertsen PC. A challenge to contemporary management of prostate cancer. Nat Clin Pract Urol (2009) 6(1):12–13.[Web of Science][Medline]

28. Bill-Axelson A, Holmberg L, Filen F, et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst (2008) 100(16):1144–1154.[Abstract/Free Full Text]

29. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med (2005) 352(19):1977–1984.[Abstract/Free Full Text]

30. Musa D, Schulz R, Harris R, Silverman M, Thomas SB. Trust in the health care system and the use of preventive health services by older black and white adults. Am J Public Health (2009) 99(7):1293–1299.[Abstract/Free Full Text]

31. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med (2003) 349(3):215–224.[Abstract/Free Full Text]

 

ournal of the National Cancer Institute [0027-8874] Brawley yr:2009 vol:101 iss:19 pg:1295 -1297

[Guest]

Another study I saw at the AAFP Annual Scientific Assembly this year randomized people with shooting pains down their legs (sciatica). Half received MRI's and half were just treated for their symptoms. The half receiving MRI's had worse outcomes. It's probably counter-intuitive that more information can be harmful, but often can be the case.

[+ purplekow]

The search for cerebral aneurysms and subsequent treatment for them in relatives of persons with a cerebral aneurysm is another example. It is unclear whether the number of aneurysms found and treated without some complication outnumbers the number of aneursyms found and treated with complications. It is also unclear as to how many left alone will eventually rupture. So advice as to what to do with the found aneurysms is very hard to determine Try talking someone out of having the tests done after their brother or sister or father or mother has just had a significant cerebral hemorrhage from an aneurysm.

 

All those whole body CT and MRI that are advertised on TV and radio are another example. The number of things found which are found at a stage where something is necessary and doable is very small. The number of things found are very large. The need for further testing once those things are found becomes a nightmare.

So do you want a screening that the medical field is strongly in favor of avoiding. At 500 to 1000 dollars a pop, people are answering yes.

All these are slippery slopes which are trod every day and which lead to large numbers of unnecessary tests being done and money being spent.

[Guest greatness]

well

 

It has been reported that sarcosine, an N-methyl derivative of the amino acid glycine, may distinguish slow-growing prostate cancers from aggressive prostate cancers. It is a very early stage to determine whether this will work. However, if it works then a non-invasive screening method can be introduced. It will be a huge thing!

 

Recently a Johns Hopkins University scientist fabricated his research on a prostate cancer screening biomarker (EPCA-2). He is under an investigation and facing a huge lawsuit. So you really have to be careful...

 

 

Nature (457, 12 February 2009: 910-914)

 

Multiple, complex molecular events characterize cancer development and progression1, 2. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.

 

 

 

 

 

 

So what progress, if any, has been made in distinguishing aggressive prostrate cancers from the slow type? Any promising research out there?

[MsGuy]

Thanks for your post, greatness. Given the cricket chirping silence that my question met, I thought I had made some kind of embarrassingly ignorant medical faux pas. To this layman it seems that a practical test to differentiate aggressive prostrate cancer from the localized type would be a real boon to both practitioner & patient.

 

My thanks to all those who have contributed to this informative thread. I've learned a lot, been led to think a bit about a subject I previously had let slide and now at least know enough to discuss the matter with my doctor should the occasion arise.

 

Also it's been delightful to peek behind the curtain and watch medical types discuss a point of disagreement. Usually we laymen only get to see a solid phalanx of white coats all solemnly nodding in unison.

[Guest greatness]

Oh MsGuy

 

You are so brilliant to think this up as a layman. A lot of biotech companies are investing a huge amount of money to come up with what you have just mentioned. If I get into a trouble you have to defend me. It would be so hot to see you defend me. The judge will just dismiss my case with prejudice after hearing your closing argument. Then I will jump out of my seat and we will share a passionate..... See below...

 

 

 

 

 

 

 

 

 

hug (G-rated).....

 

 

 

Thanks for your post, greatness. Given the cricket chirping silence that my question met, I thought I had made some kind of embarrassingly ignorant medical faux pas. To this layman it seems that a practical test to differentiate aggressive prostrate cancer from the localized type would be a real boon to both practitioner & patient.

 

My thanks to all those who have contributed to this informative thread. I've learned a lot, been led to think a bit about a subject I previously had let slide and now at least know enough to discuss the matter with my doctor should the occasion arise.

 

Also it's been delightful to peek behind the curtain and watch medical types discuss a point of disagreement. Usually we laymen only get to see a solid phalanx of white coats all solemnly nodding in unison.