April 1, 2018. In Metformin and Prostate Cancer we added: Since then a 2016 paper found, in a cross sectional study of 326 cancer-free diabetic men, that metformin lowered PSA; however, in contrast other blood glucose lowering medications (sulfonylureas, thazodlidinediones) they looked at did not lower it. This suggests that other mechanisms than blood glucose lowering are responsible. These might be androgen receptor (AR) down-regulation, other non-AR mechanisms or reduction of inflammation or reduction of lipid levels. This study also found a dose-response effect between metformin and PSA -- those who used more than 2000 mg/day of metformin had 37% lower PSA than those who used less than 1000 mg/day. See [PMID: 27403913] [Full Free Text].
A second study, this one reporting in 2017, of 1363 diabetic cancer-free men also found that metformin users had lower PSA than non-users. [PMID: 29390570] [Full Free Text].
Showing posts with label Misc. Show all posts
Showing posts with label Misc. Show all posts
Sunday, April 1, 2018
Monday, August 7, 2017
Blog Updates for July 2017
July 14, 2017. The 2017 Miror Mirror report providing international comparisons of health care systems is out and freely available [here]. The Benchmarking line under Links in the right panel of this blog has a link to it as well as links to some of their past reports.
Friday, July 14, 2017
Blog Updates for June 2017
June 6, 2017. In Metformin and Prostate Cancer we added: A June 2017 review paper by Whitburn et al on metformin and prostate cancer is available here: [PMID: 28444639] [Full Free Text]
Saturday, April 8, 2017
Finding freely available research articles
A new Firefox and Chrome browser extension creates a small button on the right
side of the screen whenever you visit a journal article's web page. If it is
green then it found the article freely and legally available on a pre-print server
or the article was not pay-walled in the first place.
To install the extension simply go the unpaywall.org site using Firefox or Chrome and click on the large button.
Once it is installed any time you visit an article it will place the aforementioned button on the right side of the screen. If green click the button to get to an open access version of the article. If the button is grey then it was unable to find a free legal source. The unpaywall.org FAQ also refers to Gold and Blue buttons but none of the sites I visited had those.
This article discusses unpaywall.org as well as some other similar sites for uncovering open access material: chronicle.com.
To install the extension simply go the unpaywall.org site using Firefox or Chrome and click on the large button.
Once it is installed any time you visit an article it will place the aforementioned button on the right side of the screen. If green click the button to get to an open access version of the article. If the button is grey then it was unable to find a free legal source. The unpaywall.org FAQ also refers to Gold and Blue buttons but none of the sites I visited had those.
This article discusses unpaywall.org as well as some other similar sites for uncovering open access material: chronicle.com.
Tuesday, January 3, 2017
Female physicians, saunas
Female vs. Male Physicians In a recent study that Harvard researchers published in JAMA, it was found that patients over 65 years old had lower death rates and lower hospital re-admission rates if they were treated by a female physician rather than a male doctor. The difference was small (11.07% vs 11.49% in adjusted 30-day mortality and 15.02% vs 15.57% in adjusted re-admissions) but if applied to the entire US population would represent a potential 32,000 fewer deaths. The study was done over the period January 1, 2011, to December 31, 2014 using a 20% random sample of all Medicare patients in this category. This represents over 1.5 million hospitalizations. Their results are consistent with a previous study [PMID: 8769910] that found that female doctors were more likely to provide preventative tests and counseling. See this [NPR article]. [PMID: 27992617] [Full Text].
Saunas A recent 20 year follow up study out of Finland found that men taking a sauna 4-7 times a week were 66% less likely to be diagnosed with dementia than those taking a sauna once a week. Not only was the effect very large but a dose response relationship was found increasing the likelihood that the effect is meaningful. (This is one of the Bradford Hill criteria for assessing studies). This follows a long list of other [claimed benefits] from saunas. See [Science Bulletin] [Abstract]
Saunas A recent 20 year follow up study out of Finland found that men taking a sauna 4-7 times a week were 66% less likely to be diagnosed with dementia than those taking a sauna once a week. Not only was the effect very large but a dose response relationship was found increasing the likelihood that the effect is meaningful. (This is one of the Bradford Hill criteria for assessing studies). This follows a long list of other [claimed benefits] from saunas. See [Science Bulletin] [Abstract]
Tuesday, November 15, 2016
2016 AUA Meeting
[Updated: December 2, 2015]
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Highlights of the 2016 American Urology Association (AUA) meeting have recently been published.
[review]
Key topics relating to prostate cancer included:
- Molecular imaging. PSMA is expressed in prostate cancer and radiotracers can detect it. The highlights include discussion of such imaging as well as the use of antibodies targeting PSMA to deliver toxic drugs directly to the cancer cells.
- Active Surveillance
- new prognostic markers aimed at distinguishing between disease having significant potential for malignancy vs. more benign disease
See the link above for the summary.
Another summary of some recent results can be found here: [PMID:27895809] [free full text]
Highlights of the 2016 American Urology Association (AUA) meeting have recently been published.
[review]
Key topics relating to prostate cancer included:
- Molecular imaging. PSMA is expressed in prostate cancer and radiotracers can detect it. The highlights include discussion of such imaging as well as the use of antibodies targeting PSMA to deliver toxic drugs directly to the cancer cells.
- Active Surveillance
- new prognostic markers aimed at distinguishing between disease having significant potential for malignancy vs. more benign disease
See the link above for the summary.
Another summary of some recent results can be found here: [PMID:27895809] [free full text]
Sunday, October 2, 2016
Blog updates for September 2016
Oct 2, 2016. In Grape Seed Extract we add: Although the 62% reduction in prostate cancer among the high grape seed extract group is eye opening there is only
one clinical trial on grape seed extract and prostate cancer: [clinicaltrials.gov - prostate cancer and grape seed extract]. In comparison there are 27 clinical trials on metformin and prostate cancer: [clinicaltrials.gov - prostate cancer and metformin] so the bets seem to be much more on [metformin] at this point.
Friday, September 23, 2016
Grape Seed Extract
[Updated October 2, 2016]
This 2011 report on the VITAL study of 35,239 men found no effect on the development of prostate cancer for chondroitin, coenzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine or saw palmetto; however, it did find a 41% reduction in the development of prostate cancer among those who took grape seed oil supplements and a 62% reduction in the development of prostate cancer among those who took doses higher than those found in multivitamins over a 10 year period. Low doses of grape seed extract, primarily from multivitamins, did not show any reduction in prostate cancer development.
There were some limitations to the VITAL study and the authors did not recommend that taking such supplements but if any of the above substances work to reduce the likelihood of the development of prostate cancer then it would seem that grape seed oil supplements would be more likely than the others. Also, the study did not look at patients who already have prostate cancer but of course if it works in one set of people it might work in another. [PMID: 21598177] [full free text].
This 2014 study of grape seed extract found an anti-cancer effect against prostate cancer cells in test tubes. [PMID: 24191894] which adds to the evidence in the VITAL study.
Although the 62% reduction in prostate cancer among the high grape seed extract group is eye opening there is only one clinical trial on grape seed extract and prostate cancer: clinicaltrials.gov - prostate cancer and grape seed extract. In comparison there are 27 clinical trials on metformin and prostate cancer: clinicaltrials.gov - prostate cancer and metformin so the bets seem to be much more on metformin at this point. For more information on grape seed extract (side effects, etc.) see the pages at drugs.com and Memorial Sloan Kettering. Additional discussion and references on grape seed extract can be found in a 2014 review of chemoprevention strategies [PMID: 24389535] [full free text] .
This 2011 report on the VITAL study of 35,239 men found no effect on the development of prostate cancer for chondroitin, coenzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine or saw palmetto; however, it did find a 41% reduction in the development of prostate cancer among those who took grape seed oil supplements and a 62% reduction in the development of prostate cancer among those who took doses higher than those found in multivitamins over a 10 year period. Low doses of grape seed extract, primarily from multivitamins, did not show any reduction in prostate cancer development.
There were some limitations to the VITAL study and the authors did not recommend that taking such supplements but if any of the above substances work to reduce the likelihood of the development of prostate cancer then it would seem that grape seed oil supplements would be more likely than the others. Also, the study did not look at patients who already have prostate cancer but of course if it works in one set of people it might work in another. [PMID: 21598177] [full free text].
This 2014 study of grape seed extract found an anti-cancer effect against prostate cancer cells in test tubes. [PMID: 24191894] which adds to the evidence in the VITAL study.
Although the 62% reduction in prostate cancer among the high grape seed extract group is eye opening there is only one clinical trial on grape seed extract and prostate cancer: clinicaltrials.gov - prostate cancer and grape seed extract. In comparison there are 27 clinical trials on metformin and prostate cancer: clinicaltrials.gov - prostate cancer and metformin so the bets seem to be much more on metformin at this point. For more information on grape seed extract (side effects, etc.) see the pages at drugs.com and Memorial Sloan Kettering. Additional discussion and references on grape seed extract can be found in a 2014 review of chemoprevention strategies [PMID: 24389535] [full free text] .
Monday, August 1, 2016
Blog updates for July 2016
July 22, 2016. In Metformin and Prostate Cancer we added statin references: Other recent work suggests benefit from combination therapy of metformin with statins [PMC3329836 full free text], [news release], p53 stabilizers [PMID: 26900800], chemotherapy [PMID: 27118574].
Wednesday, June 22, 2016
Brachytherapy problem
In a perineal saturation biopsy, a brachytherapy-like grid of rectangular squares is spaced at s = 5mm. Biopsy samples are taken. The cancer will be assumed to be a disc, i.e. circle, of diameter d. It will be detected if the disc intersects a vertex on the grid. What is the probability of detecting the cancer? of missing the cancer?
Consider a disc of diameter d around each of the 4 corners of a particular square in the grid. (See accompanying diagram.)
One quarter of each of those discs lies in the particular square so the total area of those discs within that square divided by the area of the square is the probability of detection. (This assumes a single focus of cancer d mm in diameter, that the probability distribution of its center is uniform and further assumes that the quarter discs shown in the diagram are not so large that they overlap.)
We used the fact that the area within a circle is pi*r^2 where r = d/2 is its radius. In terms of the diamter this can be written as pi * d^2/4. The above only works if the 4 quarter circles do not overlap and that is guaranteed if d is less than s. If d is greater than s then the quarter circles would overlap and adding their areas would represent double counting in the overlapping regions.
To double check we can compare the above formula to a simulation. If the cancer has a diameter of d = 2mm and each side is s = 5mm, then the probability of detecting the cancer, is 0.50265 by the formula and 0.4955 via the simulation below -- these two numbers are equal to two decimal places. We review the formula calculation and then the simulation:
1. Formula. Using the formula above and substituting in d = 2 and s = 5 we find that the probability of detection is 0.50265 (and so the probability of missing the cancer is 1 - 0.50265 = 0.49737).
2. Simulation. Using the R code at the end we create a simulation again assuming d = 2 and s = 5. d as well as s and n (number of iterations) can all be changed as needed by modifying their values near the top of the code. The code generates n = 10,000 points uniformly in an s by s square and then counts the fraction lying within d/2 of a corner as the probability of detection. This approach is more general since it also works even in the case where the discs at the 4 corners of the square overlap. Run it by copying the code below to the clipboard and paste it into the text input box at http://www.r-fiddle.org -- be sure to erase anything already in the r-fiddle text entry box first. Then press Run. (You may need to press Run twice if the answer does not appear the first time.) The code below gives the probability of detection and 1 minus that number is the probability of missing the cancer.
One quarter of each of those discs lies in the particular square so the total area of those discs within that square divided by the area of the square is the probability of detection. (This assumes a single focus of cancer d mm in diameter, that the probability distribution of its center is uniform and further assumes that the quarter discs shown in the diagram are not so large that they overlap.)
probability of detection of cancer = probability that the center of the cancer lies in one of the 4 quarter discs = (sum of 1/4 of the area of 4 discs of diameter d) / (area of one grid square) = 4 * 1/4 * (area of a disc of diameter d) / (area of one grid square) = (area of a circle of diameter d) / (area of one grid square) = (pi * (d^2)/4) / s^2
We used the fact that the area within a circle is pi*r^2 where r = d/2 is its radius. In terms of the diamter this can be written as pi * d^2/4. The above only works if the 4 quarter circles do not overlap and that is guaranteed if d is less than s. If d is greater than s then the quarter circles would overlap and adding their areas would represent double counting in the overlapping regions.
To double check we can compare the above formula to a simulation. If the cancer has a diameter of d = 2mm and each side is s = 5mm, then the probability of detecting the cancer, is 0.50265 by the formula and 0.4955 via the simulation below -- these two numbers are equal to two decimal places. We review the formula calculation and then the simulation:
1. Formula. Using the formula above and substituting in d = 2 and s = 5 we find that the probability of detection is 0.50265 (and so the probability of missing the cancer is 1 - 0.50265 = 0.49737).
(pi * (d^2)/4) / s^2 = (3.1415926 * 4^2/4) / 5^2 = 0.502652. Simulation. Using the R code at the end we create a simulation again assuming d = 2 and s = 5. d as well as s and n (number of iterations) can all be changed as needed by modifying their values near the top of the code. The code generates n = 10,000 points uniformly in an s by s square and then counts the fraction lying within d/2 of a corner as the probability of detection. This approach is more general since it also works even in the case where the discs at the 4 corners of the square overlap. Run it by copying the code below to the clipboard and paste it into the text input box at http://www.r-fiddle.org -- be sure to erase anything already in the r-fiddle text entry box first. Then press Run. (You may need to press Run twice if the answer does not appear the first time.) The code below gives the probability of detection and 1 minus that number is the probability of missing the cancer.
Thanks to Don Morris for raising this problem.set.seed(123) n <- 10000 # number of iterations in simulation s <- 5 # length of side of a grid square d <- 4 # diameter of each of the 4 discs centred at the 4 corners r <- d/2 x <- runif(n, 0, s) y <- runif(n, 0, s) mean(x^2 + y^2 < r^2 | (s - x)^2 + y^2 < r^2 | x^2 + (s-y)^2 < r^2 | (s-x)^2 + (s-y)^2 < r^2)
Friday, June 3, 2016
Blog Updates for May 2016
June 3, 2016. In Metformin and Prostate Cancer we added: A May 2016 update by Sayyid and Fleshner [PMID: 27195314] [Full Free Text] reviews studies that show a decreased prostate cancer risk with metformin as well as beneficial effects for prostate cancer patients after treatment. Other recent work suggests benefit of combination therapy of metformin with statins, p53 stabilizers [PMID: 26900800], chemotherapy [PMID: 27118574].
Saturday, April 30, 2016
Blog Updates for April 2016
Note to readers. The Palpable Prostate Blog has now published over 200 blog posts -- this post is number 201.
April 30, 2016 in Metformin and protate cancer we added: A number of investigations have concluded that metformin acts by blocking the glucose cancer cells need and in the absence of glucose they will turn to glutamanine and leucine. They hypothesize that interfering with glutamine and leucine uptake might synergistically work with metformin. Note that glutamine is a non-essential amino acid (i.e. the body can produce it itself) so simply lowering the intake of glutamine-containing foods might not be effective. [PMID: 23687346] [Free full text] [PMID: 26550231] [Full free text] [PMID: 24052625] [Full free text]
April 30, 2016 in Metformin and protate cancer we added: A number of investigations have concluded that metformin acts by blocking the glucose cancer cells need and in the absence of glucose they will turn to glutamanine and leucine. They hypothesize that interfering with glutamine and leucine uptake might synergistically work with metformin. Note that glutamine is a non-essential amino acid (i.e. the body can produce it itself) so simply lowering the intake of glutamine-containing foods might not be effective. [PMID: 23687346] [Free full text] [PMID: 26550231] [Full free text] [PMID: 24052625] [Full free text]
Thursday, March 31, 2016
Blog Updates for March 2016
March 31. In Choosing a Surgeon - Part I. Considerations, Choosing a Surgeon - Part I we added: Incidentally it has also been found that it is also true that radiation at high volume centers have better outcomes. See [PMID: 26972640] .
Thursday, February 25, 2016
Blog Updates for Feburary 2016
Feb 25, 2016. In Prostate Cancer Calculators we added this calculator: Probability of Recurrence, Potency and Continence after Laprascopic (LRP) Surgery Based on 500 LRP surgery patients of Christopher Eden this calculator accepts PSA and stage and displays the percentage of patients who were cancer-free, the percentage who regained potency and the percentage who regained continence after surgery. It also displays a table of data for all patients fitting the input parameters. The data is based on a follow up of 12 - 36 months with an average follow up of 13.5 months. The site links to a paper that provides more background detail. See theprostateclinic .
Feb 25, 2016. In Prostate Cancer Calculators we added this calculator in the Memorial Sloan Kettering section: Life Expectancy:As described and linked to in this prostatecancerinfo review "to use the tool, you will first be asked a number of questions about your health, your age, and your diagnosis with prostate cancer, and then those data are used to project your risk of death from prostate cancer and from other causes at 10 and 15 years after diagnosis.
Feb 25, 2016. In Prostate Cancer Calculators we added this calculator in the Memorial Sloan Kettering section: Life Expectancy:As described and linked to in this prostatecancerinfo review "to use the tool, you will first be asked a number of questions about your health, your age, and your diagnosis with prostate cancer, and then those data are used to project your risk of death from prostate cancer and from other causes at 10 and 15 years after diagnosis.
Tuesday, January 5, 2016
Metformin and prostate cancer
[Updated July 6, 2019]
A 2019 review and meta-analysis by Chinese researchers based on 30 research studies reported on between 2012 and 2017 concludes that metformin improves overall survival, cancer specific survival and recurrence free survival for those with prostate cancer but does not reduce the risk of getting prostate cancer for those without prostate cancer. Patients who also had radiation had even more dramatic improvements in survival. [PMID: 30778081] [Full free text]
A 2014 article in the Journal of the National Cancer Institute by Azvolinksy [PMID: 24511112] [Full Free Text] and a 2014 article by Fleshner in the Canadian Urological Association Journal [PMID: 25243043] [Full Free Text] discuss observational studies on diabetic prostate cancer patients which have shown reduced risk of death from prostate cancer as well as reduced all cause mortality among those taking the widely used inexpensive diabetes drug, metformin. A May 2016 update by Sayyid and Fleshner [PMID: 27195314] [Full Free Text] reviews studies that show a decreased prostate cancer risk with metformin as well as beneficial effects for prostate cancer patients after treatment. Other recent work suggests benefit from combination therapy of metformin with statins [PMC3329836 full free text], [news release], p53 stabilizers [PMID: 26900800], chemotherapy [PMID: 27118574].
An undated overview by Peter Wehrwein speculates that the biological mechanism may be the lowering of insulin, lowering of blood sugar output of the liver or via interruption of signalling pathways. A number of investigations have concluded that metformin acts by blocking the glucose cancer cells need and in the absence of glucose they will turn to glutamanine and leucine. They hypothesize that interfering with glutamine and leucine might synergistically work with metformin. Note that glutamine is a non-essential amino acid (i.e. the body can produce it itself) so simply lowering the intake of glutamine-containing foods might not be effective. [PMID: 23687346] [Free full text] [PMID: 26550231] [Full free text] [PMID: 24052625] [Full free text].
Since then a 2016 paper found, in a cross sectional study of 326 cancer-free diabetic men, that metformin lowered PSA; however, in contrast other blood glucose lowering medications (sulfonylureas, thazodlidinediones) they looked at did not lower it. This suggests that other mechanisms than blood glucose lowering are responsible. These might be androgen receptor (AR) down-regulation, other non-AR mechanisms or reduction of inflammation or reduction of lipid levels. This study also found a dose-response effect between metformin and PSA -- those who used more than 2000 mg/day of metformin had 37% lower PSA than those who used less than 1000 mg/day. See [PMID: 27403913] [Full Free Text].
A second study, this one reporting in 2017, of 1363 diabetic cancer-free men also found that metformin users had lower PSA than non-users. [PMID: 29390570] [Full Free Text].
A 2015 meta-analysis by Wu et al found that the risk of developing prostate cancer (as opposed to the risk of death for those who have prostate cancer) is unaffected by metformin.
Confirmation of these results in diabetics and non-diabetics through randomized clinical trails is underway. See: [ClincialTrials.gov]
A video on metformin and prostate cancer by oncologist Dr. Charles (Snuffy) Myers can be viewed here: How + When to Use Metformin.
A 2019 review and meta-analysis by Chinese researchers based on 30 research studies reported on between 2012 and 2017 concludes that metformin improves overall survival, cancer specific survival and recurrence free survival for those with prostate cancer but does not reduce the risk of getting prostate cancer for those without prostate cancer. Patients who also had radiation had even more dramatic improvements in survival. [PMID: 30778081] [Full free text]
A 2014 article in the Journal of the National Cancer Institute by Azvolinksy [PMID: 24511112] [Full Free Text] and a 2014 article by Fleshner in the Canadian Urological Association Journal [PMID: 25243043] [Full Free Text] discuss observational studies on diabetic prostate cancer patients which have shown reduced risk of death from prostate cancer as well as reduced all cause mortality among those taking the widely used inexpensive diabetes drug, metformin. A May 2016 update by Sayyid and Fleshner [PMID: 27195314] [Full Free Text] reviews studies that show a decreased prostate cancer risk with metformin as well as beneficial effects for prostate cancer patients after treatment. Other recent work suggests benefit from combination therapy of metformin with statins [PMC3329836 full free text], [news release], p53 stabilizers [PMID: 26900800], chemotherapy [PMID: 27118574].
An undated overview by Peter Wehrwein speculates that the biological mechanism may be the lowering of insulin, lowering of blood sugar output of the liver or via interruption of signalling pathways. A number of investigations have concluded that metformin acts by blocking the glucose cancer cells need and in the absence of glucose they will turn to glutamanine and leucine. They hypothesize that interfering with glutamine and leucine might synergistically work with metformin. Note that glutamine is a non-essential amino acid (i.e. the body can produce it itself) so simply lowering the intake of glutamine-containing foods might not be effective. [PMID: 23687346] [Free full text] [PMID: 26550231] [Full free text] [PMID: 24052625] [Full free text].
Since then a 2016 paper found, in a cross sectional study of 326 cancer-free diabetic men, that metformin lowered PSA; however, in contrast other blood glucose lowering medications (sulfonylureas, thazodlidinediones) they looked at did not lower it. This suggests that other mechanisms than blood glucose lowering are responsible. These might be androgen receptor (AR) down-regulation, other non-AR mechanisms or reduction of inflammation or reduction of lipid levels. This study also found a dose-response effect between metformin and PSA -- those who used more than 2000 mg/day of metformin had 37% lower PSA than those who used less than 1000 mg/day. See [PMID: 27403913] [Full Free Text].
A second study, this one reporting in 2017, of 1363 diabetic cancer-free men also found that metformin users had lower PSA than non-users. [PMID: 29390570] [Full Free Text].
A 2015 meta-analysis by Wu et al found that the risk of developing prostate cancer (as opposed to the risk of death for those who have prostate cancer) is unaffected by metformin.
Confirmation of these results in diabetics and non-diabetics through randomized clinical trails is underway. See: [ClincialTrials.gov]
A video on metformin and prostate cancer by oncologist Dr. Charles (Snuffy) Myers can be viewed here: How + When to Use Metformin.
Monday, November 30, 2015
From Pilot to System Solution
It seems that so much is known in medicine and health care that is not widely enough applied. The video below of the keynote talk by Dr. Danielle Martin at the Health Quality Transformation 2015 conference focused on health care in Ontario notes that "less than 40% of health improvement projects successfully expand beyond the early group of adopters who first bring them to life" and discusses how innovation can move from pilot to system-wide application.
It discusses the concepts of spread and scale:
- Spread is about innovations diffusing to other teams or organizations, one at a time, as successive teams learn of the successful innovation and individually decide to adopt it.
- Scale is about large scale structural change involving policies that are implemented all at once across an entire region. It requires significant resources and political capital.
She discusses the application of these concepts and many associated issues and examples.
It discusses the concepts of spread and scale:
- Spread is about innovations diffusing to other teams or organizations, one at a time, as successive teams learn of the successful innovation and individually decide to adopt it.
- Scale is about large scale structural change involving policies that are implemented all at once across an entire region. It requires significant resources and political capital.
She discusses the application of these concepts and many associated issues and examples.
Sunday, November 1, 2015
Peto's Paradox
The larger an animal is the more cells it has and the longer lived an animal has the more time cells have to mutate so one would think that larger and longer lived animals would have more cancer; however, that is not the case. Science World Report quotes researchers as saying that "less than 5 percent of elephants develop cancer compared to 25 percent of humans". That larger animals do not have higher rates of cancer is called Peto's paradox. [Wikipedia] [PMID: 21296451] [Full text] While it may be that larger animals do not get more cancer larger, or at least taller, humans have higher rates of cancer than shorter humans so this observation does seem to hold on the scale of an individual species. Evidently methods of cancer prevention have evolved in larger animals; however, taller humans may not have evolved over a sufficiently long period to elicit an evolutionary response.
We can get a bit more insight by reviewing the simple probability model of cancer developed by Calabrese and Shibata. [PMID: 20051132] [Full text] [Excel model] [Powerpoint slides] [Also see Box 2 of this paper] Assume that mutations must occur in k critical genes for cancer to occur. Assume each gene divides into d copies in its cell lineage and that there are M cells at risk in a particular organ such as the prostate -- all cells in an organ are not necessarily at risk so M is, in general, less than the number of cells in an organ. Let u be the prob of a mutation in one critical gene. Then as shown by Calabrese and Shibata (also see proof at end of this post) the probability of cancer, p, is:
p = 1 - (1 - (1 - (1 - u)^d)^k)^M
Larger animals have more cells, M, and longer lived animals undergo more cell divisions d. The number of mutations needed for cancer, k, could vary among animals and the even by the type of cancer within a species. Thus a number of other factors may be at play as well as size and life expectancy.
In the case of elephants two independent papers have concluded that they have multiple copies of the p53 tumor suppressor gene (which kills cancer cells) whereas humans only have a single set. This had been previously hypothesized; however, these two 2015 papers seem to have independently determined this to be the case.
Abegglen et al
http://jama.jamanetwork.com/article.aspx?articleid=2456041
Sulak et al
http://biorxiv.org/content/early/2015/10/06/028522
An interview with Joshua Schiffman, an author of the first paper, appears here:
http://medicalxpress.com/news/2015-10-elephants-rarely-cancer-potential-mechanism.html
In a New York Times article
http://www.nytimes.com/2015/10/13/science/why-elephants-get-less-cancer.html
Dr. Patricia Muller mentions that this research does not establish the mechanism of action so further work needs to be done even before attempting to replicate this in humans. Furthermore, the following paper: http://www.impactaging.com/papers/v2/n7/full/100178.html indicates that in
some contexts p53 accelerates aging in mice whereas in other contexts it promotes longevity so there is some question as to whether it would be feasible to apply p53 at all to humans.
Other large or long lived animals with low cancer rates might have evolved different mechanisms of combating cancer. Discovering the various mechanisms that evolved over millions of years might lead to cancer treatments in humans. Schiffman is quoted in the same New York Times article as speculating "that parrots, tortoises and whales may all have special longevity tactics of their
own". http://www.nytimes.com/2015/10/13/science/why-elephants-get-less-cancer.html
Note:
The formula given above can be derived as follows:
p = 1 - Prob of no cancer in any of the M cells at risk)
= 1 - (Prob of no cancer in one cell at risk)^M
= 1 - (1 - Prob of cancer in one cell at risk)^M
= 1 = (1 - Prob of one cell accumulating k mutations)^M
= 1 - (1 - (Prob of one mutation)^k)^M
= 1 - (1 - (Prob of mutation in 1 critical gene)^k)^M
= 1 - (1 - (1 - Prob of no mutation in one cell lineage)^k))^M
= 1 - (1 - (1 - (1 - Prob of no mutation in one of d divisions)^d)^k)^M
= 1 - (1 - (1 - (1 - u)^d)^k)^M
We can get a bit more insight by reviewing the simple probability model of cancer developed by Calabrese and Shibata. [PMID: 20051132] [Full text] [Excel model] [Powerpoint slides] [Also see Box 2 of this paper] Assume that mutations must occur in k critical genes for cancer to occur. Assume each gene divides into d copies in its cell lineage and that there are M cells at risk in a particular organ such as the prostate -- all cells in an organ are not necessarily at risk so M is, in general, less than the number of cells in an organ. Let u be the prob of a mutation in one critical gene. Then as shown by Calabrese and Shibata (also see proof at end of this post) the probability of cancer, p, is:
p = 1 - (1 - (1 - (1 - u)^d)^k)^M
Larger animals have more cells, M, and longer lived animals undergo more cell divisions d. The number of mutations needed for cancer, k, could vary among animals and the even by the type of cancer within a species. Thus a number of other factors may be at play as well as size and life expectancy.
In the case of elephants two independent papers have concluded that they have multiple copies of the p53 tumor suppressor gene (which kills cancer cells) whereas humans only have a single set. This had been previously hypothesized; however, these two 2015 papers seem to have independently determined this to be the case.
Abegglen et al
http://jama.jamanetwork.com/article.aspx?articleid=2456041
Sulak et al
http://biorxiv.org/content/early/2015/10/06/028522
An interview with Joshua Schiffman, an author of the first paper, appears here:
http://medicalxpress.com/news/2015-10-elephants-rarely-cancer-potential-mechanism.html
In a New York Times article
http://www.nytimes.com/2015/10/13/science/why-elephants-get-less-cancer.html
Dr. Patricia Muller mentions that this research does not establish the mechanism of action so further work needs to be done even before attempting to replicate this in humans. Furthermore, the following paper: http://www.impactaging.com/papers/v2/n7/full/100178.html indicates that in
some contexts p53 accelerates aging in mice whereas in other contexts it promotes longevity so there is some question as to whether it would be feasible to apply p53 at all to humans.
Other large or long lived animals with low cancer rates might have evolved different mechanisms of combating cancer. Discovering the various mechanisms that evolved over millions of years might lead to cancer treatments in humans. Schiffman is quoted in the same New York Times article as speculating "that parrots, tortoises and whales may all have special longevity tactics of their
own". http://www.nytimes.com/2015/10/13/science/why-elephants-get-less-cancer.html
Note:
The formula given above can be derived as follows:
p = 1 - Prob of no cancer in any of the M cells at risk)
= 1 - (Prob of no cancer in one cell at risk)^M
= 1 - (1 - Prob of cancer in one cell at risk)^M
= 1 = (1 - Prob of one cell accumulating k mutations)^M
= 1 - (1 - (Prob of one mutation)^k)^M
= 1 - (1 - (Prob of mutation in 1 critical gene)^k)^M
= 1 - (1 - (1 - Prob of no mutation in one cell lineage)^k))^M
= 1 - (1 - (1 - (1 - Prob of no mutation in one of d divisions)^d)^k)^M
= 1 - (1 - (1 - (1 - u)^d)^k)^M
Tuesday, September 29, 2015
Blog Updates for September 2015
Sep 27, 2015. In Prostate Cancer Calculators we added:
- Date of Death The population.io web site asks for your birthday, country and gender and based on this input estimates what percentage of people in your country and on earth are younger than you and your date of death.
- Mortality Simulator The flowingdata web site shows a chart with a blue curve part way down the page. The curve represents the probability of living for at least another year given your age. The probability is on the vertical axis and age is on the horizontal axis. Moving dots traverse the blue curve representing lifetimes of a single person. They drop off the curve at death and accumulate in piles below the curve. These piles represent the distribution of life spans.
Saturday, August 1, 2015
Blog updates for July 2015
August 1, 2015. In PSADT Part 1 we add:
PSA Doubling Time (PSADT) was found to be the most consistent of the top prognostic factors for a variety of endpoints (prostate cancer-specific survival, metastases-free survival, overall or all cause survival) in a 2015 literature review of relevant studies so we focus this 5 part series of posts specifically on it. [PMID: 26180662] [Full Free Text]. (The other consistent key factors were Gleason Score and Time to Biochemical Failure.)
Wednesday, July 1, 2015
Demographic Factors Affecting Prostate Cancer Mortality
In a June 25, 2015 PLoS One paper [full text] Yao et al perform a
regression of prostate cancer mortality (one point per county) using the
following explanatory variables:
Significant at 0.1% level:
- more urologists per 100,000 people decreases prostate cancer mortality
- being in a metropolitan country decreases prostate cancer mortality
- greater percentage of population being non-white increases prostate cancer mortality
- greater percentage of population with high school diploma decreases prostate cancer mortality
Significant at 1% level:
- greater prostate cancer incidence per 100,000 men increases prostate cancer mortality
Significant at 5% level:
- if county is a designated Health Professional Shortage Area it increases prostate cancer mortality
- if per capita income is higher then it reduces prostate cancer mortality
Factors that were not significant were:
- radiation oncologists per 100,000 people
- beds per 100,000 people
- percent of population over 65
Significant at 0.1% level:
- more urologists per 100,000 people decreases prostate cancer mortality
- being in a metropolitan country decreases prostate cancer mortality
- greater percentage of population being non-white increases prostate cancer mortality
- greater percentage of population with high school diploma decreases prostate cancer mortality
Significant at 1% level:
- greater prostate cancer incidence per 100,000 men increases prostate cancer mortality
Significant at 5% level:
- if county is a designated Health Professional Shortage Area it increases prostate cancer mortality
- if per capita income is higher then it reduces prostate cancer mortality
Factors that were not significant were:
- radiation oncologists per 100,000 people
- beds per 100,000 people
- percent of population over 65
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