Having just devoted an entire Doc Gumshoe piece to the notorious coronavirus (COVID 19), I’m going to make those coronavirus updates brief – it looks to me as though the news media is devoting a major part of its capacity to covering most aspects of this pandemic – and, yes, it now certainly looks like a pandemic, even though WHO has so far not said so. However, WHO has elevated the threat posed by this virus to the maximum.
So, first, to a couple of topics that came up in the comments to the previous piece.
What about the Inovio COVID 19 vaccine?
Lots of antennae went up when Inovio announced that they had found a vaccine that could work in the coronavirus, after just a few hours of research. Possible or impossible?
There are several steps in the development of a vaccine, and Inovio may have taken the first, which would be to determine whether their proposed vaccine had the necessary characteristics to mimic the target coronavirus. That’s the first and essential step in developing a vaccine. The candidate vaccine informs the host’s immune system that there’s a potential invader out there with certain genetic characteristics, so that if such an invader presents itself to the host, the host will mobilize its immune system to repel the invader.
In its first few hours of research, the Inovio team may have indeed determined that their proposed vaccine might have that capacity. But there are several more steps that would need to be ascended. Very early in the development of a vaccine, it would have to be definitively determined that the candidate vaccine did not cause an infection in the host, which, if it bore much resemblance to the virus itself, it well might. As perhaps you know, the vaccine that gave vaccination its name, the vaccine derived from cowpox (Latin “vacca” means “cow”), which very effectively prevents smallpox infections, almost always causes a mild infection in the host, but not a full-fledged smallpox infection. And many people have reactions to flu shots. So making sure that the coronavirus vaccine did not itself produce COVID 19 will be an essential and time-consuming step.
Even more time consuming, and just as essential, will be making sure that the candidate coronavirus vaccine really does prevent infection with the particular coronavirus that causes COVID 19. That will take considerable time, and the results are by no means certain.
In the meantime, in addition to the three candidate vaccines that I mentioned in my previous piece, at least one more attempt to develop a vaccine is underway. Glaxo SmithKline has entered the race, working with a Chinese company, Clover Pharmaceuticals.
A few more COVID 19 items
To a question from a reader about the coronavirus in Italy, I had responded that as of that date, there were three confirmed cases in Italy, and that was that. Since then, the spread in Italy has been very fast and of great concern. As of today, there are 1,694 confirmed cases and 34 fatalities.
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Another piece of decidedly bad news is that several instances have been found where the coronavirus was transmitted from an asymptomatic person. This means that just because the person with whom you are in proximity appears to be totally healthy that does not mean that he/she couldn’t be infecting you with COVID 19.
At this point in the US at least one person with a confirmed case of COVID 19 seems to have had no direct contact with anyone who came from China or any other region where the cases have spread. It is possible that the transmission of the virus was at several removes – that is, person A transmitted it to person B who transmitted it to person C and so on, and none of the transmitters were symptomatic. Currently, there are 86 confirmed COVID 19 cases in the US, and there have been 2 fatalities.
Up to this point in this epi/pandemic, it appears that men are more likely to be infected by the coronavirus than women. This may be because women appear to have a more active immune system than men. Having a more robust immune system may be a mixed blessing for women, since it appears to make women more susceptible to immune-related diseases such as rheumatoid arthritis, lupus, and psoriasis. The fatality rate for women with COVID 19 is also significantly lower than for men. At the time the news item about women’s decreased risk of infection was written, the fatality rate for women was about 1.9%, while for men it was 2.8%. Those figures will need to be revised upward, since the current combined fatality rate appears to be 3.2%.
A factor that is likely to have considerable effect on efforts to contain the disease is that up to this point, testing for the virus has been done only in CDC laboratories, which entails sending samples to the lab and waiting at least a couple of days for results. Many local boards of health, including the New York Board of Health, have testing facilities which are totally up to the mark, and could turn around the test results in a few hours, which would make the containment of COVID 19 very much more manageable. Putting every individual suspected of being infected with the coronavirus into quarantine while waiting for the CDC test results puts the entire system under considerable strain, and since anyone with anything resembling the coronavirus symptoms should be tested, that would mean potentially quarantining everyone who comes down with any upper respiratory infection. At this moment, the CDC is in negotiation with local authorities to move the testing to the local level – in other words, closer to where the signs of outbreak may be emerging.
An interesting bit of related news is that because many drugs, including both generic and branded drugs, are either made in China or depend on materials that come from China, the FDA has compiled a list of drugs whose availability may be affected by the shutting down of Chinese manufacturing facilities due to COVID 19. The FDA has singled out 20 of these drugs that may become scarce, but has asserted that alternatives are available for all these agents. The contents of the list have as of now not been made public.
My thanks, by the way, to a reader who sent me this curious link, from Spirit Daily:
“Unnerving it is when a book foresees the future. The Bible is one thing—filled with prophecy. But secular books? Do they occasionally stumble on the future by accident? Jules Verne saw a giant “space cannon” shooting something in Florida. Was it on that stretch of shore later called Cape Canaveral, site of the Kennedy Space Center? Sci-fi king Arthur C. Clarke foresaw virtual reality.
Most recently, it has come to light that a thriller novel by horror writer Dean Koontz called The Eyes of Darkness, written in 1981, mentioned a virus called Wuhan-400. In the novel, the virus was created as a weapon in a laboratory. Some claim that’s the case in the current outbreak. (We recommend against reading any of his horror books.)”
Was the coronavirus created in a lab in China to attack us? Or was it created in that same CIA lab the set HIV loose to “purify” the US population? Weird theories abound!
Regardless of what I am covering in future Doc Gumshoe pieces, I will keep COVID 19 firmly in my sights.
Some additional reports from the front:
Overall cancer mortality versus prostate cancer mortality
In the midst of good news about cancer mortality in general, there emerged bad news about prostate cancer mortality. The good news first: cancer death rates have declined 29% from their peak in 1991 to 2017, the most recent year for which data are available, according to the American Cancer Society (ACS).
Prostate cancer mortality, on the other hand, is on the rise. ACS had some good news about prostate cancer, notably that between 1991 and 2017, prostate cancer deaths declined by 52%. But the good news is coming to an end. ACS predicts that 192,000 cases of prostate cancer will be diagnosed in 2020, up from174,000 in 2019. And the death toll from prostate cancer in 2020 is predicted by ACS to reach 33,000 – the highest number of fatalities in 20 years.
This has led to a minor war between the American Cancer Society and the Prostate Cancer Society (PCS). PCS takes credit for practically every advance in prostate cancer treatment. Here’s what they say: “PCS has funded nearly every practice-changing development in the field, including early investment in 11 life-saving or life-extending drugs in oncology.” (That leaves out ACS, NIH, and the National Cancer Institute.) PCS lays the blame for the increase in prostate cancer diagnoses on the aging of the baby boomers.
In contrast, the ACS and the major prostate cancer charities point to the recommendation by the U. S. Preventive Services Task Force against routine use of prostate-specific antigen (PSA) testing for prostate cancer because of growing concerns about over-diagnosis and over-treatment. As a result, prostate cancer diagnosis plummeted between 2007 and 2014. And as a result of the reduction in the number of diagnoses, fewer men received early treatment for prostate cancer, and if they had cancer, the cancer was more likely to progress to a later stage and to result in more deaths.
The principal focus of PCS is late-stage treatment for prostate cancer, and they have indeed made valuable contributions in that sphere. But encouraging a practice that results in fewer diagnoses of early-stage cancers, and thus the development of more late-stage cancers, should not be part of its mission.
About a month ago, the Journal of the National Cancer Institute published the results of a study that had clearly been meant to show that less frequent screening for prostate cancer would result in significant reductions in overdiagnosis as well as cost savings, with no appreciable difference in outcomes. (Heijnsdijk EAM et al. J Natl Cancer Inst. 2020 Jan 9. pii: djaa001)1 Here’s the conclusion from the study:
“Relative to a biennial screening strategy, PSA-stratified screening strategies investigated in this study substantially reduced the testing burden and modestly reduced overdiagnosis while preserving the majority of lives saved. Further research is needed to clarify the link between PSA growth and disease progression.”
The key word in that conclusion, in Doc Gumshoe’s view, is “majority.” But taking a closer look at the results of the study reveals a different picture. The study was based on an analysis of data from a cohort of men in Sweden aged 45 to 69, and compared with data from the Malmö Preventive Project (MPP), which stored serum and tracked subsequent prostate cancer diagnoses for 25 years.
Compared with biennial PSA testing, the group calculated that if men with PSA levels under 1.0 ng/mL at age 45 were screened every 8 years instead of every 2 years, then approximately 47% fewer tests would be done and there would be approximately 1-2% fewer overdiagnoses. However, approximately 3-4% fewer lives would be saved using this approach.
Another model, where instead screening was stopped altogether at age 60 if levels were below 1.0 ng/Ml, was estimated to result in up to 24% fewer overdiagnoses but as many as 13% more deaths compared with continued biennial PSA screening until age 69.
In response to that paper, William Catalona, MD, a well-known authority in prostate cancer screening, was quoted in MedPage Today as follows:
“In my practice, I now see daily the sad effects on men who have had a hiatus in their PSA testing or have not been tested because their doctors have told them that PSA testing caused more harm than good. I believe that the message of this paper suggesting that less PSA testing is desirable could compromise many men.”
These were not quite the results that the study sponsors were anticipating, but they bear out the general principal that detecting a disease, whatever it is, at an early stage leads to a better outcome. No matter how skillful the clinicians become at managing late-stage cancers, we’re better off zapping them when they are new.
Refinements in cancer surgery
According to the American Society of Clinical Oncology (ASCO), refinement of cancer surgery was recognized as ASCO’s 2020 “Advance of the Year.” Howard A. Burris, MD, ASCO’s president, noted that for a long time, surgery was the only treatment for many cancers, but the rapid growth of systemic cancer treatment has had a large impact on surgery, in some cases minimizing or eliminating the need for surgery, but also greatly improved the effectiveness of surgery.
Specifically cited were improvements in the treatment of melanoma, kidney cancer, and pancreatic cancer.
For melanoma, the standard treatment for many years was surgical removal of the tumor and most nearby lymph nodes. A recent study in Australia demonstrated that giving patients with stage IIIC melanoma-specific targeted therapies before surgery led to responses in 86% of patients and complete responses in about half. The pre-operative therapy made the tumors easier to remove, and the results were consistent with an earlier study with the same targeted therapies, which showed a six-fold increase in event-free survival compared with patients who had surgery with no pre-operative therapy. The drugs used in these studies were dabrafenib (Tafinlar) and trametinib (Mekinist), both from Novartis.
In another trial, investigators achieved similar results with a combination of ipilimumab (Yervoy) and nivolumab (Opdivo), both from Bristol-Myers Squibb. The chief difference between the studies employing these two drug pairings was that the patients receiving the Yervoy/Opdivo combination experienced fewer adverse events than those receiving the Tafinlar/Mekinist combination. However, both pre-operative targeted drug treatments led to major improvements in patient outcomes.
In metastatic renal cell carcinoma (a form of kidney cancer), the results of two separate clinical trials provided convincing evidence that surgery might be avoided altogether. Does this qualify as a “refinement in cancer surgery?” I’m not sure, but it certainly qualifies as a distinct boon to the patients in question.
In one trial, patients received the drug sunitinib (Sutent, from Pfizer) and then were randomized either to have surgery or to omit the surgery. Median overall survival was 18.4 months in patients who received sunitinib alone versus 13.9 months in those patients who also had surgery.
A second trial evaluated patients with primary clear cell metastatic renal cell carcinoma. One group was treated with sunitinib and delayed surgery, while the other group had surgery up front followed by treatment with sunitinib. The median overall survival rate was more than twice as long with sunitinib up front and then delayed surgery – 32.4 months versus 15.0 months.
In pancreatic cancer, surgery continues to give patients the best odds for survival. Unfortunately, many patients at diagnosis have cancers that are unresectable. However, data from two studies point to pre-surgical drug treatment that considerably improves the odds of such patients when surgery is attempted. One of these employs a combination therapy dubbed Folfirinox, which consists of four chemotherapy agents: folinic acid (leucovorin calcium), fluorouracil, irinotecan hydrochloride, and oxaliplatin.
A trial was conducted in 48 patients with pancreatic cancer whose likelihood of experiencing a successful surgery was borderline. All patients received the Folfirinox combination therapy, and of these, 31 went on to have surgery. The results pointed to significant benefit. Patients who had surgery had a median progression-free survival of 48.6 months, and median overall survival has yet to be reached. Two-year overall survival in patients who underwent surgery was 72%, versus 56% for all patients.
In another study, the antihypertensive losartan (Cozaar) was added to the Folfirinox regimen, which also resulted in increasing the median overall survival in the patients who went on to have surgery.
In all three of these cancer forms, it was not the surgical technique itself that resulted in the improvement in outcomes, but the use of chemotherapy in combination with therapy that had those positive results.
Aspirin use reduces cancer mortality in older folks
This is based on a very large study, published this last December in JAMA Network Open (Loomans-Kropp HA et al, JAMA Netw Open. 2019 Dec 2;2(12)). A total of 146,152 persons with a median age of 66.3 years at baseline were followed from screening, which began in 1993, and continued through follow-up and analysis, which was completed in September 2019. The four outcomes evaluated were all-cause mortality; mortality due to any cancer; gastrointestinal cancer; and colorectal cancer.
Aspirin use one to three times per month was associated with a 16% reduction in the risk of all-cause mortality, and a 13% reduction in the risk of cancer mortality. In those subjects who took aspirin three or more times per week, the reduction in the risk of all-cause mortality increased to 19%, and a 15% reduction in cancer mortality. The risk of GI cancer was reduced by 25%, and the risk of colorectal cancer was reduced by 29%.
A secondary analysis looked at whether the effects of aspirin use on cancer mortality were affected by the body-mass index (BMI) of the individual. The risk reduction was precisely the same among persons with a BMI in the normal range, 20 to 24.9, and those in the overweight range, 25 to 29.9.
There has been, as Gumshoe denizens likely know, considerable back-and-forth about aspirin’s benefits versus risks. The principal risk associated with aspirin is bleeding in the GI tract, resulting from aspirin’s anti-clotting effect. This is precisely the basis for a principal benefit of aspirin, which is that it may lower the risk of stroke. There is solid evidence that in persons who have already experienced a stroke or a TIA (transient ischemic event), aspirin lowers the risk of a follow-on stroke (secondary prevention). For primary prevention – that is, in individuals who have not had a previous incident, the benefit is not quite so clear.
The USPSTF, which Doc Gumshoe has railed against many times in these manifestos, currently recommends low-dose aspirin for the prevention of both cardiovascular disease and colorectal cancer only among persons from ages 50 to 59 at average risk for cardiovascular disease. From ages 60 to 69, they suggest treatment should be individualized. And they made no recommendations for aspirin use in individuals 70 years of age and older, citing insufficient evidence.
For my part, I’m sticking with my daily baby aspirin.
A new approach to combating Alzheimer’s disease?
It keeps coming up, and it’s more of a threat that COVID 19, for which I’m sure that both a vaccine and a bona fide cure will be developed.
This approach accepts the hypothesis that the clumping of amyloid in the brain is a fundamental factor in the progression of Alzheimer’s disease. Not necessarily the fundamental factor, but a fundamental factor. This, despite the failure of any number of agents that targeted this mechanism.
The way several drugs have tried to prevent the formation of those clumps that gum up the works in our brains has been by blocking gamma secretase, an enzyme that binds to the precursor protein to form amyloid. These drugs, so far, have not produced anything like the desired effect, although as Doc Gumshoe has noted in these dispatches, Biogen is still betting on their aducanumab horse.
A scientist at Rensselaer Polytechnic may have found a way to get around the gamma secretase inhibitor’s numerous failures. After screening millions of compounds in a computer search, he identified a compound that forms a permanent bond to the cleavage site of the protein which is a precursor to gamma secretase itself. The candidate compound blocks amyloid production in test tubes and cell culture.
Will preventing the formation of amyloid in the brain prevent Alzheimer’s-related dementia? We’ll just have to wait and see.
In the meantime, there are continuing instances of persons whose brains on autopsy are clogged with amyloid, but who showed no trace of dementia. Some people are quick to conclude that amyloid has nothing to do with Alzheimer’s disease, while others (Doc Gumshoe included), attribute it to cognitive reserves.
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I’ll bolster my cognitive reserves by doing the necessary sleuthing and writing these pieces. And you, dear readers, by reading them and sending me interesting comments! Best to all, Michael Jorrin (aka Doc Gumshoe)