So, is the cardiovascular disease risk really lower for patients with an LHRH antagonist then an LHRH agonist for ADT?

Both LHRH agonists and LHRH antagonists can be used for androgen deprivation therapy. A commonly used LHRH antagonist is the drug Firmagon (degarelix) and is administered as a monthly depot injection. Compared to the LHRH agonist drugs, such as Lupron (Leuprorelin) or Zoladex (goserelin), degarelix suppresses testosterone faster and supposedly carries lower risk of cardiovascular disease (CVD). However, it requires two injections when patients start on it and the depot injections last only a single month. It is not uncommon that patients, who have a high PSA at diagnosis, start on degarelix and then shift over to an LHRH agonist drug, where injection can last three months or more. All these drugs are equally effective in suppressing testosterone.

Early on there was some data suggesting that the risk of a serious CVD in the form of a myocardial infarct (MI; what we commonly call a heart attack) was lower for the antagonist than the agonist. But does this hold up for all major CVDs? This includes MIs, strokes, ischemic heart disease (IHD; where the heart muscle is not getting enough oxygen leading to pain that often radiated to the left shoulder), arrythmia, and heart failure.

We finally have a comprehensive review that looks at the specific risk factors for these various CVDs for patients on LHRH agonists versus LHRH antagonist and the results are intriguing. The antagonist is indeed associated with less risk of heart failure, particularly for patients, who have had prior CVD when starting on ADT. There is a different story though for men with no prior history of CVD. For them, the antagonist was associated with a decreased risk ischemic heart disease, but an increased risk of arrhythmia.

All of this points towards a need for a rigorous cardiovascular assessment for patients starting on ADT. The best drug for each patient depends on their cardiac status, history, and the need for rapid androgen suppression.

Reference:

Dragomir, A., Touma, N., Hu, J., Perreault, S., & Aprikian, A. G. (2023). Androgen Deprivation Therapy and Risk of Cardiovascular Disease in Patients With Prostate Cancer Based on Existence of Cardiovascular Risk. Journal of the National Comprehensive Cancer Network : JNCCN, 21(2), 163–171.

https://pubmed.ncbi.nlm.nih.gov/36791755/

Is There Still a Context for using Bicalutamide (Casodex) as Monotherapy for ADT?

Although it is not used this way in North America, there are places where the first generation oral antiandrogen, bicalutamide (Casodex), is used as a monotherapy for ADT. Because this drug blocks the receptors for androgens, the serum testosterone levels for patients on bicalutamide monotherapy remain high.

Excess testosterone is naturally converted to estrogen. As a result, men on this treatment regime are less likely to experience hot flashes, osteoporosis, and a total loss of their sex drive, which are all due to loss of estrogen in men on LHRH drugs. However, estrogens cause breast development and discomfort in the breast is a common side effect of bicalutimide as monotherapy.

Because of some toxicity and limited survival benefit, bicalutimide monotherapy is now not a common ADT protocol in Europe, although it is still approved there to treat prostate cancer. The patients best served by this ADT protocol are those who find the side effects of the LHRH drugs particularly difficult to tolerate yet need androgen blockade to control their prostate cancer.

Against this background, we have a new paper, which seems to us as anachronistic. The paper addresses a way to avoid breast discomfort for patients on bicalutimide monotherapy. This is to provide the patients with prophylactic radiation to the breasts. To be clear, this protocol has been around for decades, but is used less commonly in recent years. Now, bicalutimide is typically used short term in order to prevent testosterone flares when patients start on LHRH agonist drugs. The breast problems are reduced by using the bicalutimide short term. This avoids a need for any prophylactic radiation, and avoids the risk of cardio-toxicity from the radiation and the risk of a secondary, radiation-induced cancers.

The authors describe gynecomastia for prostate cancer patients as “a frequent disabling side effect of antiandrogen therapy….[and along with breast pain]… can significantly affect a patient's quality of life.” They do not provide a reference for this, but other research that they do not cite suggests that the distressed from these breast symptoms are highly variable among men who are on ADT treatments that promote breast development. Admittedly, some men find the breast symptoms very distressing while but others find them of little bother.

What is most odd about this paper is why the patients were on any drugs at all. Out of the sample of 76 men (with the mean age of 74 years), who were then followed for one to five years, 2/3 of the men had a Gleason scores of six or lower. Similarly, over 2/3 of the men had a PSA value of less than 10.

As noted in the title of paper, these men had a low to intermediate risk of prostate cancer mortality. Increasingly these men would be advised to go on active surveillance without any prostate cancer treatments. As such, they would not need any additional treatments to mitigate the side effect of the drugs.

So, why are these patients being put on bicalutamide monotherapy? According to the authors, some of the men were too frail and had too many comorbidities to be good candidates for surgery. Others were reluctant to give consent for external beam radiation or found this treatment took too long. Others evidently feared radiation-related morbidities. On that last point, it would seem better that the men simply delayed active treatment rather than go on bicalutimide monotherapy.

By both current North American and European guidelines, the majority of men in this study did not warrant starting on ADT of any form.

Reference:

Chernomordikov, E., Rouvinov, K., Mermershtain, W., & Lavrenkov, K. (2023). Prophylactic Breast Irradiation for Prevention of Bicalutamide-induced Painful Gynecomastia in Patients with Low- and Intermediate-risk Prostate Cancer. The Israel Medical Association journal: IMAJ, 25(3), 205–209.

Hormone Intensification—If Two Drugs are Good are Three Drugs Better?

In the last few years there have been a slew of studies involving standard ADT (i.e., with LHRH agonists or antagonists) combined with other drugs to treat various prostate cancer populations. These populations include both patients whose cancer is hormone sensitive as well as those who are castrate resistant. 

The drugs that are being combined with ADT included both taxane chemotherapy and various androgen receptor targeting agents (ARTAs; i.e., the second generation anti-androgens and abiraterone plus prednisone). The studies are so numerous now that it is hard to keep them all straight. Thus, it is a joy to see a pros and cons discussion of the merits of the various drug combinations in ESMO-OPEN, a journal of the European Society for Medical Oncology.

The patient population addressed in the in the ESMO-Open paper are men with metastatic prostate cancer that can still be controlled with hormonal therapy. The relatively new standard of care for these patients is ADT plus an ARTA. That would be a form of doublet therapy. Another doublet therapy though would be ADT combined with chemotherapy.

The authors present the cases, both for and against going with triplet therapy in the form of ADT + an ARTA + chemo for this patient population. With overall survival as a primary outcome, the authors conclude that this “up front triplet combination …will become a new standard of care for fit men with de novo metastatic hormone sensitive prostate cancer”.

However, when discussing the case against triplet therapy, the authors point out that in much of the world these men will have been previously treated for localized disease and they should be distinguished from those who are first diagnosed with metastatic, but still castrate sensitive, disease. The men, who have been pretreated for localized disease, are likely being followed closely with PSA tests and may have a relatively low tumor burden when diagnosed with metastatic disease. The authors argue this should be taken into consideration when deciding to move from doublet to triplet therapy. Given the heightened adverse side effect risk in tripled therapy, these patients may be better off staying on a doublet therapy protocol. All of these treatments have substantial side effects burdens and thus the overall health of the individual patient, such as the risks of hypertension and liver toxicity, should be taken into consideration when moving from doublet to a triplet therapy.

We are optimistic that there will be substantial refinements in the next few years about when it is best to use hormone intensified treatments and which treatments will be best for specific patient populations. A driving factor here is the availability of higher quality imaging of tumors and improvements in tumor targeted treatments. Treatment protocols are also likely to change as we learn more about the genetics behind metastatic prostate cancer and get a better sense of when to start a patient on triplet therapies given their genetic profile and comorbidities.

Reference:

Oing, C., & Bristow, R. (2023). Systemic treatment of metastatic hormone-sensitive prostate cancer-upfront triplet versus doublet combination therapy. ESMO open, 8(2), 101194.

https://doi.org/10.1016/j.esmoop.2023.101194

Are the Side Effects from ADT Different for Men of Asian Versus African or European Ethnicity?

In general men from Asian ethnic groups are less likely to die of prostate cancer compared to men from European or African ethnic groups. Studies from individual Asian countries have established that generally, Asian men have a better baseline metabolic profile compared to Caucasian prostate cancer patients. Several studies have shown, for example, that Asian men are less likely to have severe cardiac events on ADT and may be able to tolerate multiple rounds of chemotherapy with less toxicity than those of Caucasian background.

Note though that in the last paragraph we mention studies from individual Asian countries. How broad reaching are these ethnic generalizations?

There's a new study that looks at the adverse metabolic responses to ADT for men from several Asian countries. The study followed 589 patients for a year or more from Hong Kong, the People's Republic of China, Taiwan, and Malaysia. The average age of the men was 72 years.

Within six months, the men showed significant increases in fasting glucose levels and in hemoglobin A1c indicative of increased risk of diabetes. Similarly, their triglyceride levels were elevated and on average they gained 1 kilogram in weight within a year and a half of starting on ADT. These are common signs of metabolic syndrome seen in men on ADT from European and African ethnic groups.

The Asian patients thus show similar metabolic shifts to those seen in men from other continents and ethnicities, although not quite as severe. The Asian men in general are not as likely to be overweight as, say, North American prostate cancer patients and that may account substantially for the Asian men doing better on ADT.

Large population studies of health and ethnicity, like this one, will be increasingly important as we learn more about the genetics of prostate cancer progression. Studies like this can help us find genetic biomarkers of disease development and hopefully identify treatments that are most effective for men of diverse genetic backgrounds.

Reference:

Wong, C., Xu, N., Lim, J., Feng, K., Chan, W., Chan, M., Leung, S., Chen, D., Lin, Y., Chiu, P., Yee, C., Teoh, J., Huang, C., Yeoh, W., Ong, T., Wei, Y., & Ng, C. (2023). Adverse metabolic consequences of androgen deprivation therapy (ADT) on Asian patients with prostate cancer: Primary results from the real-life experience of ADT in Asia (READT) study. The Prostate, 10.1002/pros.24519.

https://doi.org/10.1002/pros.24519

Nutrient Guidance for Patients on ADT

The European Association of Urology just published a short paper summarizing dietary recommendations for men on ADT. As  a context for this paper the authors note that,  “dietary interventions for mitigating ADT side effects are promising, but few interventions have focused on diet alone and they offer limited evidence of benefit.”

The authors thus acknowledge that there has not been much research on diet specific for men on ADT. They also write, “longer-term studies that incorporate longitudinal compliance measures and collect progression outcomes or intermediate biomarkers of prognosis are needed in cancer patients, and specifically in patients treated with ADT.” That's a fancy way of saying that we need more research on compliance.

The authors flag a study that is underway and looks at whether a digital platform can help support patients who try to make lifestyle changes while receiving ADT. Their study recognizes that the challenge is not so much about getting relevant nutritional information to patients, but in getting patients to comply with the recommendations.

The paper has two interesting tables.

The first one lists recommendations for preventing heart disease and for reducing cancer death overall, including prostate cancer death. It is noteworthy that the data are not specific to men on ADT, but are nevertheless in line with the recommendations in the ADT book on a heart healthy diet for men on ADT.

The second table lays out a few of the questions that patients might ask about diet when starting on ADT. And it offers some answers to those questions. These include recommendations relevant to avoiding osteoporosis and weight gain. The table also informs patients that evidence for benefit from supplements is negligible, except perhaps for vitamin D and calcium (plus vitamin B12, if one is on a vegan diet.)

What is interesting is a discrepancy between Table 1 and Table 2. In terms of alcohol consumption for heart health, Table 1 recommends limiting one’s alcohol consumption to one or two drinks per day…and avoiding it completely, if one wants to reduce the risk of dying from cancer in general. The table also suggests limiting alcohol consumption to five or less drinks per week, to reduce the risk of lethal prostate cancer.

Table 2 has a more lenient and perhaps more realistic recommendation, which is prefaced with: those who aren't drinking, obviously shouldn't start. However, for those that do like to drink, recommendations are to limit one’s intake to one or two drinks per day.

Despite these inconsistencies, the authors do a good job laying out what we know and need to know in order to arrive at helping men on ADT maintain the best nutritional status.  At the moment, there is no easily managed diet for overcoming most of the detrimental metabolic side effects ADT.

Reference:

Kenfield, S., Van Blarigan, E., Graff, R., Borno, H., Macaire, G., & Chan, J. (2023). Nutrition Guidance for Patients on Androgen Deprivation Therapy. European Urology Focus, S2405-4569(23)00060-3.

https://doi.org/10.1016/j.euf.2023.02.009

ADT and the Kidneys

Listed among the rare side effects of ADT is acute kidney injury (AKI). One does not hear much about that though, presumable because it is rare. But what is behind that risk? Is it rare–like some rare allergic reactions, which some people never experience, but for others are life threatening?

There is now a review by a urologist in Japan on how ADT might lead to impaired kidney function. This paper helps demystify the risk of AKI.

AKI is an extreme form of renal impairment and, as the author points out, some level of renal impairment can occur with dyslipidemia. So, what is dyslipidemia? Dyslipidemia is an unhealthy level of the triglycerides and high- and low-density cholesterol in one's blood. Dyslipidemia is associated with diabetes and is part of the type of metabolic syndrome that has been associated with ADT, and the elevated risk of diabetes for men on ADT.

We often talk about how ADT, if not properly managed, can increase the risk of diabetes. In the same way that a poor lipid profile puts men at risk of diabetes, it can increase the risk of renal impairment. This doesn't get discussed often because it typically goes unnoticed…unless it is severe and presents itself as AKI and, in the extreme, as kidney failure.

For the same reason that we need a good lifestyle to avoid the risk of diabetes when on ADT, the same precautions can help avoid renal impairment. Another way to view this is that patients on ADT should maintain a lifestyle that avoids dyslipidemia, not only because of the risk of cardiovascular disease and diabetes, but also because it helps preserve good kidney function.

The author ends with simple recommendation about language and we think it is a good one. There he states: “With regard to lipid dysfunction due to ADT, the term ‘renal impairment’ should be used instead of ‘AKI’”.

Reference:

Masuda, H. (2023). Renal Impairment: A Major Adverse Event in Prostate Cancer Patients Treated With Androgen Deprivation Therapy. Anticancer Research, 43(1), 305-309.

Are Too Many Old Men With Prostate Cancer Going on ADT?

According to a group of urologists in Italy, the answer is “yes”.

Residing in Europe, the authors reached that conclusion based on the formal guidelines for the use of ADT set out by the European Association of Urology. Those guidelines are clear that with no sign of systemic disease, and with a low PSA and a long PSA doubling time, there is no benefit in putting elderly patients on ADT. These guidelines also state that it is inappropriate to put such men on ADT, if they have not yet received, but could safely receive, treatment for localized disease.

Following those guidelines, the researchers found that out of 427 elderly patients, who were treated with ADT, 66 (15.5%) started on ADT when they shouldn't have. These were all elderly men. Many were identified as “old old”; i.e., over 75 years old.

The paper rigorously reviews the serious cardiovascular side effects that can come from ADT, such as a heart attack and osteoporosis, as well the most bothersome ones, such as fatigue and hot flashes. Given the potentially dangerous side effects of ADT in the elderly population, a case can be made to avoid ADT when there is little sign that the patients will benefit from the treatment.

Although the paper does not go into this, one might imagine that these men are not good candidates for a radical prostatectomy, but that would not rule out external beam radiation, which could be an alternative to starting them prematurely or unnecessarily on ADT. The authors also point out that excessive use of ADT has a large financial cost on the health care system.

There is no reason to suppose that excess use of ADT is a problem specific to Italy. We have personally seen men with a very low and slow climbing PSA well over 75 anxious to start ADT. Given their climbing PSA, they fear that they must start ADT as soon as possible…regardless of other factors that could influence their overall survival. It would be interesting to survey such patients and find out why they are more worried about prostate cancer than having a heart attack, a stroke, or falling down and breaking a hip from osteoporosis. Although this is only a speculative guess, we suspect that the word “cancer” is interpreted as more threatening to the men then many of  of the health risks associated with the side effects of ADT.

This paper is a great review of the side effects of ADT, but it also raises the question of why a large percentage of men are started on this treatment when they don't benefit from it. Are the clinicians recommending it excessively or are the patients demanding it excessively? To be clear, although we see great benefit in the appropriate use of ADT for extending the lives of men with advanced prostate cancer, we know of no great benefit for older men to start on it without clear evidence that the benefits out rank the risks.

Reference:

Oderda M, Bertetto O, Barbera G, Calleris G, Falcone M, Filippini C, Marquis A, Marra G, Montefusco G, Peretti F, Gontero P. Appropriateness and complications of androgen deprivation therapy for prostate cancer: Can we do better? A retrospective observational analysis from a referral center. Urologia. 2023 Jan 26:3915603221149502. doi: 10.1177/03915603221149502 Epub ahead of print. PMID: 36703243.

Does ADT Increase the Risk of Alzheimer’s Disease?

Approximate 200 papers in the medical literature over the last six years have commented on a possible association of long-term ADT with dementia for prostate cancer (PCa) patients. We have reviewed some of those papers in previous blog entries. Yet the papers keep coming out and some have seemingly contradictory conclusions. Here are two examples:

“Cumulative ADT exposure was associated with dementia.” [Lonergan et al. 2022] 

“Androgen deprivation therapy was associated with a significantly decreased risk of AD for men with prostate cancer.” [Du & Song, 2023; note “AD” stands for Alzheimer’s disease]

The first paper sounds bad, but the second one sounds surprisingly good. So, what is going on here?

The Du & Song study was a retrospective look at data from the SEER database linked to a Medicare database in the USA. It included information on 350,000 men diagnosed with PCa, who were all over the age of 65. Some had been on ADT and some also had an AD diagnosed. A separate epidemiological study by Lehrer & Rheinstein (2023) using data form the UK’s Biobank reached a similar conclusion. Both studies suggested that ADT does not cause Alzheimer’s disease and may even be associated with lower risk of that disease. Both studies depended on large registry files with formal neurological diagnoses, plus drug prescription data to define the study populations.

The conclusion that ADT doesn’t cause AD may seem somewhat problematic considering that many studies suggest that long term ADT may lead to some cognitive impairment. To make sense of these papers one needs to realize that Alzheimer’s disease is a specific form of cognitive impairment. Both the Du & Song and Lehrer & Rheinstein papers distinguish Alzheimer’s disease from a variety of other forms of dementia. AD is one form of dementia, but there are others.

A patient who says, after starting on ADT that he is more likely to misplace his car keys or glasses may never be diagnosed with any form of dementia, as that sort of daily cognitive challenge is common with aging. Occasional “senior moments” are not classified as clinically significant dementia. They are just common with aging and are not likely to be recorded in databases like the SEER, which relies on rigorous criteria for neurological diagnoses.

Age turns out to be a key factor here. As we get older, we are all likely to show some signs of cognitive impairment. That is a sad reality of aging, but in and of itself is not a definitive sign of AD. Notably the PCa patients on ADT were on average older than the patients not on ADT. However, if ADT helps men live longer, then they are more likely to experience some decline in cognitive function over time.

Conversely, if AD shortens one’s life expectancy, then it will be less likely to be linked to long term use of ADT. The complicating variable here is that ADT use and the emergence of AD are both more common with old age, but not necessarily causally linked to each other.

So, does ADT cause cognitive impairment? A variety of studies, but not all of them, would say “yes”, as there is some statistical association at the population level between cognitive performance and the long-term use of ADT. But that does not mean that all men on ADT will experience cognitive impairment and it may not show up at all, if they are relatively young and otherwise healthy.

Does ADT specifically increase the chances of getting AD? The data on that suggests the answer is “no”. That is particularly true if they are relatively young and otherwise healthy.

References:

Du, X.L., Song, L. A (2023) Large Retrospective Cohort Study on the Risk of Alzheimer’s Disease and Related Dementias in Association with Vascular Diseases and Cancer Therapy in Men with Prostate Cancer. J Prev Alzheimers Dis. https://doi.org/10.14283/jpad.2023.8

Lehrer S, Rheinstein PH. (2023) Androgen Deprivation Therapy Unrelated to Alzheimer's Disease in the UK Biobank Cohort. Anticancer Res. 2023 43(1):437-440. doi: 10.21873/anticanres.16179. PMID: 36585167. 

Lonergan PE, Washington SL 3rd, Cowan JE, Zhao S, Broering JM, Cooperberg MR, Carroll PR.  (2022) Androgen Deprivation Therapy and the Risk of Dementia after Treatment for Prostate Cancer. J Urol.  207(4):832-840. doi: 10.1097/JU.0000000000002335

Does ADT increase the risk of getting COIVD? – Nope.

It is nice when the title of a medical paper is in the form of a complete sentence and tells the main story of the paper. A new study out of Sweden managed to do just that.

The paper is titled “Androgen deprivation therapy in men with prostate cancer is not associated with COVID-2019 infection.” Covid 2019 in Sweden is what most people in North America now simply call COVID; the disease caused by the SARS-CoV-2 virus.

Early on during the COVID pandemic, there was a lot of discussion about whether prostate cancer (PCa) might increase (or decrease) the risk of getting the infection. There was similar concern about whether treatments for PCa influenced the risk of getting the infection or the severity of it once acquired. 

This new paper involved a comparison of 224 PCa patients treated with ADT, 431 PCa patients who had not been treated with ADT, and 240 men diagnosed with just benign prostatic hypertrophy.

The authors found no association between ADT use in prostate cancer patients and subsequent risk of SARS-CoV-2 infection, nor of the severity of the disease for men who caught it. The authors did, however, find that obesity and having type 1 diabetes increased the risk of getting COVID.

This appears to us to be a relatively clean study, but the sample size was not large enough to know whether men who are on ADT and subsequently get diabetes were also at increased risk of severe COVID. That has, though, been reported in other studies.

The take-home messages here is that one should not worry about being at increased risk of getting COVID, if one is on ADT. However, they should be concerned if they’re not taking precaution, while on ADT, to avoid excessive weight gains that get them into the obese range on put them at risk of becoming diabetic.

Reference:

Davidsson, S, Messing Eriksson, A, Udumyan, R, et al. Androgen deprivation therapy in men with prostate cancer is not associated with COVID-2019 infection. Prostate. 2023; 1- 8. doi:10.1002/pros.24485

It is Not Necessarily Metabolic Syndrome that You Should be Worried About…

Most of us on ADT have experienced some weight gain and loss of muscle mass. Those are two conspicuous features of what is called metabolic syndrome (MetS). MetS is defined by a suite of features that include not just those two conspicuous features, but also a shift in blood markers related to lipids, cholesterol, and the risk of diabetes. One doesn’t need to have all of the features of MetS to be considered at risk of developing MetS. As PCa patients, we are warned that ADT carries a risk of MetS and that one should maintain a healthy lifestyle (exercise and diet) to minimize the risk.

Against that background, there’s a new paper out that does a meta-analysis of previous studies on ADT and comes up with a surprising result. There the author reports that “ADT was not associated with the development of MetS”.

One needs to remind themselves that it is not MetS per se that is the issue, but rather it is indicative of elevated risk for certain serious cardiovascular diseases such as hypertension and diabetes. In that regard, the paper concluded that men have a 25% increased risk of developing diabetes and a 30% increased risk of developing hypertension while on ADT. That’s serious stuff.

How could this paper find that the patients on ADT are less likely to develop MetS, yet still are at increased risk of hypertension and diabetes? It seems like a contradiction.

When one digs into the paper, a few factors show up that can account for this.

For example, the authors note that for some studies included in their analysis, it wasn’t clear what form of ADT the patients were on. Secondly, the studies were done from around the world. One needs to remind themselves that MetS is not one thing, but a suite of things…and one doesn’t have to present with all of them to be classified as having MetS. So, for example, for one population, weight gain may be the most common sign of MetS and in another , a shift in triglycerides may be more prominent. The authors didn’t document that specifically, but the studies included in the meta-analysis were from around the world and the authors acknowledged the high variability in their data, which may account for why they found less evidence of MetS.

Of course, that isn’t what really matters. It’s the long-term risks of the serious stuff like hypertension and diabetes that we need to be concerned about. In this regard, the authors are firm on their recommendations and we endorse them. Men starting on ADT need to be assessed for cardiac function and diabetic risk.

In addition, along with getting regular PSA tests, men should also get their haemoglobin A1c checked as a blood marker for diabetes, a cardiac assessment, and track their blood markers for MetS (triglycerides and cholesterol).

It isn’t the MetS that you need to worry about. It’s the cardiovascular and metabolic risks that need to be monitored, on any form of ADT.

Reference:

Swaby J, Aggarwal A, Batra A, Jain A, Seth L, Stabellini N, Bittencourt MS, Leong D, Klaassen Z, Barata P, Sayegh N, Agarwal N, Terris M, Guha A. Association of Androgen Deprivation Therapy with Metabolic Disease in Prostate Cancer Patients: An Updated Meta-Analysis. Clin Genitourin Cancer. 2022 Dec 26:S1558-7673(22)00264-6. doi: 10.1016/j.clgc.2022.12.006. Epub ahead of print. PMID: 36621463.