Mostly Non-COVID-19 Related Miscellany

Some updates from Doc Gumshoe on Hydroxychloroquine, Aspirin for cancer, stem cells for Parkinson's and CRISPR for blindness

By Michael Jorrin, "Doc Gumshoe", June 11, 2020

It’s not as though the pandemic has cleared the decks of all other health-related issues.   I’m sorry to report that people still have heart attacks, strokes, and cancer as well as all the plethora of other ailments, diseases, and conditions that affect our species.   For example, I was thinking of putting in a phone call to my orthopedist, because I seem to have pulled a back muscle while lifting soggy bags of mulch to spread in the garden.   I’m happy to report that I don’t have to at this moment, because my wrenched muscle seems to have relaxed a good deal – happy not only because my back feels a lot better, but also because I don’t have to be sitting in the doctor’s waiting room when some infected person wanders in spreading the evil virus.

But, as it happens, the pandemic has apparently had a quite significant effect on the numbers of people seeking care for those other, non-COVID-19 ailments.   A close friend of ours who was scheduled for a total knee replacement (TKR) in March of this year had her procedure postponed for the time being. 

Postponing TKR is highly unlikely to lead to severe consequences to life or health, other than the discomfort and pain of continuing to hobble around on a creaky knee until the surgery can be safely done, and the patient goes through the necessary (and painful) rehab process.   In the case of our friend, both the surgery itself and the rehab posed the risks of fairly close physical contact with persons who might have been infected with the corona virus although not yet showing symptoms, so the deferment of her surgery was a sound move.

However, non-treatment of other conditions can have dire results.   For example, a new study from Beth Israel Deaconess Medical Center in Boston suggests that a considerable number of patients may have put off emergency care for such issues as heart attacks and strokes.   It is not known why these patients did not seek emergency care, but a likely supposition is that they were wary of becoming infected with the corona virus and simply avoided going to a hospital emergency department, where presumably there would be significant numbers of patients with symptoms suggesting a corona virus infection, and therefore, probably highly contagious.

The Beth Israel study found that in March and April of this year, there was a 33% drop in the number of patients presenting to the emergency department with heart attacks, compared with the same period in other years.   A much larger drop – 58% — in the number of patients with strokes was characterized as “stunning” by one of the authors of the study, Dr Dhruv Kazi, director of Beth Israel’s Cardiac Critical Care Unit and a Harvard Medical School faculty member.

It’s possible that some of this drop may be due to changes in the living conditions of the population during the pandemic.   Many more people have been staying at home, perhaps eating better, working out more often, not feeling stressed about commuting to work in heavy traffic.   And air quality has gotten somewhat better.   But those changes are nowhere near enough to account for large differences in the numbers of patients presenting with what certainly might be life-threatening health conditions.   And at the same time, recently released data suggest that concerns about the pandemic and its effects on the economy are resulting in increased levels of anxiety and stress in the general population.

Similar drops in the numbers of patients seeking treatment for conditions that would normally unquestionably bring patients to hospital emergency departments have been seen in places like Northern California and Italy.   The perception that the disease caused by this virus is exceedingly infectious and frequently fatal, and the widespread news that hospitals are swamped with a tidal wave of dangerously infectious patients has persuaded patients that in spite of symptoms that would otherwise have led them immediately to seek treatment, they are better off taking the chance that they will weather their symptoms than risking infection with the virus. 

Dr Kazi emphasized that hospitals needed to do a better job convincing patients that their risk of contracting the corona virus infection, when presenting at a hospital for urgent care, was very small.   He pointed out that hospitals have extensive experience with infection control in emergency room settings.   In an interview, he was quoted as follows:   “Very quickly, for instance, we split our emergency room into a section that would care for people with respiratory complaints that might be COVID-19 and an entirely separate section that dealt with individuals who clearly did not have complaints resembling COVID-19. In the COVID-19 section of the emergency room, patients were masked immediately, and clinicians took ample precautions to ensure there was no risk of transmission from patients to clinicians or among patients. This went into place even before the first trickle of patients started showing up in our emergency rooms. So, the risk was very, very low from the get-go.”

The COVID-19 pandemic has had major effects on the ability of patients with other conditions to receive necessary treatment.   For example, the American Cancer Society Cancer Action Network initiated a survey on April 30th to get a sense of the delays and cancellations in health care services and economic challenges affecting their ability to pay for care and their future ability to access and afford the care they need.   The most alarming finding was that 79% of patients in active treatment for some form of cancer reported delays in their treatment including chemotherapy, radiation, or hormone therapy.   A total of 87% of respondents to the survey reported some change, delay, or disruption to their health care as a result of the pandemic including not only care related to their cancer, but care for chronic and ongoing conditions, and regular preventive health care.   The survey did not clarify whether the delays and disruptions were primarily due to patients’ fears of corona virus infection or other pandemic-related issues, such as a widespread avoidance by health care providers of in-person visits.

No doubt, minimizing person-to-person proximity is an important part of preventing transmission of the corona virus.   On the other hand, the risk of non-treatment of heart attacks, strokes, and cancer is considerable.

Another COVID-19-related item

In previous Doc Gumshoe pieces there has been discussion of the disputed merits of those malaria drugs, hydroxychloroquine (HCQ)and chloroquine (CQ), strongly touted by the Presidents of both the US and Brazil, but strongly questioned by most knowledgeable authorities in the treatment of infectious diseases.   At this point, the US President has publicly stated that he’s off HCQ.   That’s probably because of the study published in The Lancet which evaluated the outcomes of 96,032 patients with COVID-19 who were treated at 671 hospitals in 6 continents.  (Mehra MR. The Lancet 5/22/20).   

Patients who received CQ or HCQ, either alone or in combination with azithromycin, were compared with patients on none of these treatments.   Mortality was 9.3% in patients receiving neither drug, 16.4% and 18.0% in patients receiving either CQ or HCQ respectively, and 22.2% and 23.8% in those receiving either CQ or HCQ in combination with azithromycin.   Evidently, neither CQ nor HCQ did anything to prevent death in COVID-19, but these drugs were independently associated with increased risk of death and increased risk of cardiac arrhythmias, especially torsade de pointes, a frequently fatal arrhythmia.   And then, on June 1st, the World Health Organization decided to suspend a trial of HCQ for COVID-19 due to safety concerns.    

The President of Brazil has not made any moves away from HCQ as far as we know. 

A late-breaking addendum to that bit of news is that a few days after The Lancet paper was published, a group of about 100 scientists and clinicians wrote a letter to The Lancet’s editor, questioning the authenticity of the huge hospital database on which the paper was based.   The company that owns that database is Surgisphere, an outfit in Chicago that has access to worldwide patient records.   The owner of Surgisphere, Dr Sapan S. Desai, responded, stating that Surgisphere is certified by the International Organization for Standardization and audited by independent third party auditors.   “Our strong privacy standards are a major reason that hospitals trust Surgisphere, and we have been able to collect data from over 1,200 institutions across 46 countries”, Dr Desai said.

It’s hard to know whether the scientists who sent that letter are favoring HCQ over alternative treatment options, or merely raising doubts about the data behind The Lancet paper on principle.   My guess is the former.

Last minute bulletin on this subject: WHO announced that they will indeed resume their trial of HCQ.   

And one more last minute bulletin: on June 5th, The Lancet announced that the paper mentioned above was retracted.   Here is their statement:

“Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements.   As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process.”

Yet more late-breaking addenda

It was not only the Lancet paper that was retracted.   A paper in the New England Journal of Medicine, by the same authors and based also on Surgisphere data was also retracted.   The finding of the NEJM paper was that there were no adverse effects of ACE inhibitors on patients with COVID 19.   

In connection with both the Lancet and NEJM papers, an unpaid faculty member at the University of Utah, Dr Amit Patel, who had been a co-author on both papers, and had also introduced the lead author to Dr Desai of Surgisphere, was removed from his post. 

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In the light of that, I need to retract my statement that in my view, the 100 experts who sent the original letter to the editors of the Lancet were more motivated by their favoring HCQ than by doubts about the validity of the Surgisphere data.   Evidently, their doubts were genuine.

Finally, there is more news about HCQ that might once and for all put an end to that particular controversy.   A study based on data from more than 11,000 patients in 175 hospitals in the UK reported no indication of survival benefit in hospitalized COVID-19 patients.   In fact there was a non-significant trend toward increased risk of death in patients taking HCQ versus usual care.   Mortality was 25.7% in patients taking HCQ compared 23.5% in usual-care patients.   The study, RECOVERY, was supported by the health officers of the UK and conducted by the University of Oxford.   

I would venture that this study puts the kibosh on hydroxychloroquine as treatment for COVID-19.

More about aspirin

Aspirin, as we know, has several potentially beneficial effects beyond reducing pain.   It reduces inflammation by inhibiting cyclooxygenase, the enzyme that synthesizes prostaglandins, which are important mediators of inflammation.   It acts to bring down fevers through much the same mechanism.   And it also inhibits the formation of blood clots by latching on to thromboxanes in the blood stream, those being the agents that bind to blood corpuscles and get them to form clots.

What we probably didn’t know is that aspirin is active in lowering the risk of several gastrointestinal cancers.   This was based on pooled data from 113 studies.   The benefit from taking one or two low-dose aspirin per week was significant.   The degree of risk ranges from a 22% reduction in pancreatic cancer to reductions of over 33% in esophageal and stomach cancers, and 38% in liver cancer.   

The authors also calculated the number of deaths that could be avoided in the EU if the use of aspirin were to increase.   Lead author Carlo La Vecchia, MD, of the University of Milan was quoted as follows:

“There are about 175,000 deaths from bowel cancer predicted for 2020 in the EU, of which about 100,000 will be in people aged between 50 and 74.   If we assume that regular use of aspirin increases from 25% to 50% in this age group, this would mean that between 5,000 to 7,000 deaths from bowel cancer and between 12,000 and 18,000 new cases could be avoided if further studies show that aspirin does indeed cause the reduction in cancer risk.   Corresponding figures would be approximately 3,000 deaths each for esophageal, stomach and pancreatic cancer, and 2,000 deaths from cancer of the liver.”

Another finding in the pooled studies was the correlation between the reduction in colorectal cancer risk and the aspirin dose.   An aspirin dose between 75 and 100 mg a day was associated with a 10% reduction in a person’s risk of developing cancer compared to people not taking aspirin; a dose of 325 mg a day was associated with a 35% reduction, and a dose of 500 mg a day was associated with a 50% reduction in risk.   It was noted, however, that the estimate for high-dose aspirin was based on just a few studies and should be interpreted cautiously.

Dr Emmanouil Pappou of Memorial Sloan Kettering concurred that the study was supported by observational analyses showing risk reduction in colorectal cancer associated with aspirin use.   However, he pointed out that a person has to take aspirin for a long time, at least 10 years, for any protective effect to kick in.

Dr La Vecchia added that “Taking aspirin for the prevention of bowel cancer, or any other cancers, should only be done in consultation with a doctor, who can take account of the person’s individual risk. This includes factors such as sex, age, a family history of a first-degree relative with the disease, and other risk factors. People who are at high risk of the disease are most likely to gain the greatest benefits from aspirin.”

An experimental treatment for Parkinson’s using pluripotent stem cells

The immediate cause of Parkinson’s disease and Parkinsonism is the loss of dopamine-producing neurons in the brain.   Doc Gumshoe described this in considerable detail in “About Parkinson’s,” which posted on April 1st.   The first attempt to replace dopamine neurons by transplanting them into the brains of Parkinson’s patients took place in the 1980s.   Surgeons used neurons from the brains of aborted fetuses, as many as 16 fetuses per patient.   In spite of the fact that many physicians viewed these procedures as unethical, they were performed on a number of patients.   It has never been clear that these procedures were beneficial in the long term.   The surgery itself – the physical intrusion into the patient’s brain – seems to trigger a surge of dopamine in the brain, resulting in a short-term surge of freedom from the chains of Parkinson’s.   However, long-term benefits of any kind were minimal; most of the transplanted cells were short-lived.

Kwang-Soo Kim, a stem cell biologist at McLean Hospital in Boston, believed that the source of stem cells should not be fetuses, and also not embryonic stem cells, but the patient’s own cells.   As long ago as 2009 he published a paper describing how to turn connective cells from the patient’s own skin into induced pluripotent stem cells.   These cells, iPS cells, have the capacity to morph into any of the body’s specialized cells, whether heart, liver, muscle, or brain cells.   Pluripotent means that they have multiple potential, including the potential to morph into the dopamine neurons in the brain whose demise brings on Parkinson’s.

The original methodology for the generation of iPS cells was devised by Shinya Yamanaka, who used a standard laboratory virus as the vector to carry four genes into the connective skin cells to reprogram them as iPS cells.   For this work, Yamanaka received a Nobel prize in 2012.   However, a number of researchers had serious doubts about using a virus as the transport mechanism for the reprogramming genes.   If they landed in the wrong place, they might inactivate the genes that suppress tumors or activate cancer-causing genes.   

As an alternative, Kim was able to produce the four genes that Yamanaka had identified within E. coli bacteria, purified them, and attached them to a small molecule.   That molecule eventually – after much intensive experimenting – was found to be able to penetrate the harvested skin cells and turn them into iPS cells.   Most important, those pluripotent stem cells easily turned into the midbrain dopamine neurons that Kim had hopes would be a viable treatment for Parkinson’s. 

A vital ally in this quest was George Lopez, himself formerly a practicing physician, whose advancing Parkinson’s had greatly limited his life.   He became familiar with Kim’s work and offered to fund its further development.   With the funding from Lopez, Kim hired a team of assistants and was able to overcome the next obstacles that had hampered the transition of iPS cells from a laboratory victory into a bona fide treatment for Parkinson’s.   An important obstacle to overcome was that even as the iPS cells turned into dopamine neurons, a small percentage of the iPS cells would remain undifferentiated, threatening the effectiveness of the procedure.   They searched a database of compounds for something that would target a gene termed “surviving,” which is abundant in the undifferentiated iPS cells.   Eventually they identified a Chinese herbal compound, quercetin, which completely removed the remaining iPS cells, leaving only the dopamine neurons.

Numerous trials were then conducted in rats whose dopamine-making cells had been obliterated with a neurotoxin.    These trials demonstrated that the transplanted dopamine neurons were functional.   The research had progressed to the point that using this method in a human patient would be feasible. 

The human patient in which this strategy was first attempted was this same George Lopez.   By the time Kim and his team were ready to test their method in a human subject, Lopez’s Parkinsonism had progressed considerably.  He had given up most of his physical activities; he could no longer go spearfishing and his mountain bike had been retired.   He was in nearly constant pain, and he had to struggle to lift himself out of a chair.

Kim recruited Dr Jeffrey Schweitzer, who had been recommended to him by his own neurologist as “the best neurosurgeon,” and Schweitzer accepted the role.   In January of 2017, the FDA granted the team a “compassionate use” protocol, approving a one-patient trial.   In preparation for the surgery on Lopez, Schweitzer developed a motor-driven syringe to keep the iPS cells from emerging from the needle in a single blob, which he thought had been a problem in previous attempts to introduce stem cells into the brains of laboratory animals.   The cells formed one big ball, which gave the cells no access to nutrients or oxygen.  

In the surgery, four million of the dopamine neurons were injected into Lopez’ brain.   As the motor-driven syringe was pulled back from the brain, it expelled the neurons in a thin line.   When Lopez emerged from anaesthesia, he immediately felt a surge of renewed energy, and was able to walk a considerable distance without help.   This, however, was not because of the dopamine neurons implanted in his brain.   The immediate effect on Lopez was likely due to the physical effects of the surgery: introducing an instrument into the brain immediately causes the release of a great amount of dopamine.  The act of surgery itself kills a certain number of cells, which then quickly release all their dopamine.

The FDA had insisted that the surgery on Lopez be limited to one hemisphere of his brain, so that, in the case of a mishap in the surgery, the other hemisphere at least would be unharmed.   After the immediate dopamine surge receded, and Lopez’s energy surge also receded, it was decided to repeat the procedure on the other hemisphere.

Eighteen months after the second surgery, Lopez was carefully evaluated by a neurosurgeon at Mass General Hospital, who said that he had demonstrated a number of areas of functional improvement that “are hard to argue with.”   For example, before the surgeries, he had given up wearing shoes with laces, because his fingers were not nimble enough to manage the laces.   But that ability had returned.   Also, he sent his surgical team a video of himself swimming across a pool – an activity that he had been forced to give up for fear that he would drown.

Some of researchers involved with this experiment expressed concern that some of Lopez’s improvement may have been due to a placebo effect – having undergone two brain surgeries, Lopez deeply wanted it to work.   

The research team has met with the FDA to discuss the design of a clinical trial to verify whether this specific mode of stem cell therapy might work in Parkinson’s.   And it has been pointed out that doing iPS cell transplants for every Parkinson’s patient would be hugely expensive.   But the principle, once validated, could certainly lead to new options for Parkinson’s management.   More economical ways of producing the iPS cells will likely be developed, and the surgery itself is not necessarily any more expensive than other procedures that are now common.

This may eventually be the breakthrough that Parkinson’s patients have been waiting for.

CRISPR as a treatment for a rare genetic disease that causes blindness in children

The disease is Leber congenital amaurosis, which accounts for about 20% of blindness in school-age children.   The prevalence of this disease is not firmly established; various sources put it at anywhere between 1 in 33,000 and 1 in 100,000 children.   It was first identified in the 19th century by Theodor Leber, who was one of the founders of modern ophthalmology.   “Amaurosis” means darkening, and that is essentially what happens to the vision of the babies born with this disease.   From the very beginning of their lives, their vision dwindles.   Leber congenital amaurosis (LCA) particularly affects the retina, which is the tissue at the back of the eye that receives the light entering the eye through the cornea.   The retina detects light and transmits the shapes and colors to the optic centers of the brain.   

The symptoms of LCA are numerous.   As the disease progresses in babies and children, they experience photophobia, which is a difficulty in looking at bright lights.   They also have several other symptoms, including rapid involuntary eye movements, cataracts, crossed eyes, dislocation of the eyeballs, abnormal retinal pigment, extreme farsightedness, and pupils that do not react normally to light.   In many cases, the disease culminates in blindness.       

A form of gene therapy using an adenovirus, voretigene neparvovec (the trade name is Luxturna, developed by Spark Therapeutics) was approved by the FDA in 2017.     It has been shown to be somewhat effective in the treatment of LCA in patients in whom the cause of the condition is a mutation in one specific gene, RPE65.   The estimated cost for a one-time treatment protocol is $850,000, and further safety and efficacy studies will be required.   It should be noted, however, that LCA is associated with mutations in more than a dozen genes other than RPE65.   

A basic cause of Leber congenital amaurosis is a gene mutation that prevents the formation of a protein that is needed to convert light into signals to the brain, which is fundamental to sight.   Babies with LCA are often born with very little vision, and within just a few years, even that defective vision is gone, and the children are totally blind.

Researchers at Editas Medicine are developing a CRISPR-based treatment for LCA in conjunction with Allergan.   Standard gene therapy, which would be based on transporting the necessary gene by means of a viral vector, is not an option, because the required gene is too large to fit inside the disabled virus particles that are used to ferry the gene into cells.   The Editas plan is to delete the mutation by making cuts in the gene’s DNA on either side of the mutation, with the expectation that the two ends of the DNA will reconnect and let the gene function as it is supposed to.

The procedure is done in a one-hour surgery, in which a very small amount, no more than three drops, of the fluid containing the gene-editing machinery is transported to the retina.  The researchers believe that somewhere between one tenth and one third of the mutated genes need to be edited in that way to restore vision.   They believe that this goal is attainable, since in animal studies, about half of the mutated cells were corrected with this treatment. 

In case you’re wondering why Doc Gumshoe picked those topics …

I included these highly experimental treatments – the surgical treatment for Parkinson’s and CRISPR gene-editing to that rare mutation causing blindness in young children – not because it was likely that either of these would become mainstream medicine, but because it shows just how medical research is pushing back the obstacles that prevented treatment of many diseases and conditions that have previously been thought to be beyond the limits of what medicine could deal with.   As you probably know, gene editing, by whatever means, is constantly in increasing use for a wide range of medical conditions and diseases.    

There was a Doc Gumshoe posting back on December 5, 2019 (doesn’t that seem like a long, long time ago?) that attempted to lay out, in clear terms, the way CRISPR and CAR-T work.   I notice that in the news items that I come across, mentions of CRISPR and CAR-T are strewn about with scarcely a syllable of explanation of how they work.   Perhaps the journalists don’t want to waste the time/space on explanations that they think a lot of the folks they’re addressing either don’t need or don’t care about.   Perhaps they don’t feel confident about their own level of understanding.   I acknowledge that getting to the bottom of these complex processes takes a deep dive indeed, and I question whether I can hold my breath long enough to go as deep as I need to.  But I try and will keep on trying.          

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To all Gumshoeland denizens, many thanks for all the comments.   Your comments are not only welcome, but useful – they keep me on the qui vive, so to speak, and also alert me to subjects that I should consider investigating.   So, thanks again!

Michael Jorrin (aka Doc Gumshoe)

(Ed. Note:  Michael Jorrin, who I dubbed “Doc Gumshoe” many moons ago, is a longtime medical writer (not a doctor) who shares his thoughts on health and medicine with our readers a couple times a month.  He does not offer personal health or investment advice, and does not generally write about investment ideas, but has agreed to our trading and disclosure rules.  You can see all of his past columns here.)