Interesting double blind study on Muscadine Grape Skin Extract and PCa

[FRTHBST]

This kind of study indicates the difficulties in wading through complexities of diet and cancer. In this case the authors propose that the biophenols in the grape skin were responsible for significantly increasing psadt. Though only for those of certain genotypes. These are the kind of studies we need to clarify why certain phytochemicals seem to be of great benefit for one person, while for the next may be of no help or even deleterious.

clincancerres.aacrjournals....

[Hidden]

You said: "In this case the authors propose that the biophenols in the grape skin were responsible for significantly increasing psadt" but the article you posted actually says: Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses.

I think you might want to read it again.

I did some more research and found another article from the Journal of Clinical Oncology on the same trial (NCT01317199)

ascopubs.org/doi/abs/10.120...

[FRTHBST in reply to Hidden]

Right- except if you read the section on page 311, SOD2 genotype analysis. There's some subtlety in their findings. "High-dose Ala/Ala patients experienced a10.3-month medianincreaseinPSADT(P¼0.11) whilelow-dose patients experienced a 2.8-month median increasein PSADT (P¼0.08)"

Then in the Discussion on the following page:However, in a protocol-defined subset analysis of PSADTchange in patients with theSOD2Ala/Ala genotype, patientswho were treated with MPX experienced a significant 6.4-monthmedianincreaseinPSADT(P¼0.02), while patientson the control arm experienced a 1.8-month median increase inPSADT (P¼0.25).TheincreaseinPSADTwasgreaterinthehigh-dose MPX arm (10.3 months) than in the low-dose arm(2.8 months).

The point is that in a subset of patients with a specific genetic marker, PSADT increase was significant.

[Hidden in reply to FRTHBST]

Again, from your article: Exploratory analysis revealed a patient population with potential benefit that would require further study. (emphasis is mine)

Doesn't sound like it's proven to me.

[FRTHBST in reply to Hidden]

Yes, I agree. The benefit for the subgroup came up in the context of a study that was designed to look for a broader result. The interesting point is that in the context of a double blind placebo controlled study(albeit a small one ), a significant effect on PSADT was found that warrants further study. Double blind studies of potential phytochemical treatments are few and far between. While the old joke; If you're a researcher who can't cure cancer in mice, you need to find a new job, still obtains, the number of suggestive lab studies involving polyphenols continues to pile up. With a disease like cancer where the etiology is most often not well defined or understood, it might be important not to dismiss any information. I still think that it's interesting.

[Tall_Allen]

It shows the opposite of what you said:

"Compared with placebo, MPX did NOT significantly prolong PSADT in BCR patients over two different doses."

[FRTHBST in reply to Tall_Allen]

Right- except if you read the section on page 311, SOD2 genotype analysis. There's some subtlety in their findings. "High-dose Ala/Ala patients experienced a10.3-month medianincreaseinPSADT(P¼0.11) whilelow-dose patients experienced a 2.8-month median increasein PSADT (P¼0.08)"

Then in the Discussion on the following page:However, in a protocol-defined subset analysis of PSADTchange in patients with theSOD2Ala/Ala genotype, patientswho were treated with MPX experienced a significant 6.4-monthmedianincreaseinPSADT(P¼0.02), while patientson the control arm experienced a 1.8-month median increase inPSADT (P¼0.25).TheincreaseinPSADTwasgreaterinthehigh-dose MPX arm (10.3 months) than in the low-dose arm(2.8 months).

The point is that in a subset of patients with a specific genetic marker, PSADT increase was significant.

[Tall_Allen in reply to FRTHBST]

The subset was 27 patients in who had the alanine/alanine [AA} genotype of SOD2. SOD2 encodes manganese superoxide dismutase (MnSOD) the primary mitochondrial enzyme that protects cells from oxidative stress. I chuckled when I read that because that is exactly the same Hail Mary play used by the researchers on pomegranate juice (which had no effect).

"Though the study failed to demonstrate an overall PSADT treatment effect statistically different from that seen in the placebo arm, data from a preplanned analysis of the current study showing statistically significant prolongation of PSADT in MnSOD AA patients treated with pomegranate compared with controls suggest that patients with the AA genotype of the MnSOD gene may represent a subpopulation of patients that is particularly susceptible to the effects of antioxidants."

nature.com/articles/pcan201532

In fact, if you look at any highly colored fruit (blueberries, cranberries, etc.) I'm sure you will find a similar benefit to this aberrent subgroup. (although whether it translates to any long-term benefit is highly questionable). The moral - if you have been diagnosed with this genetic abnormality, you should include highly colored fruits in your diet. Or even if you don't have this mutation, include highly colored fruits in your diet.

[FRTHBST in reply to Tall_Allen]

Good point! I'll stand by my original comment that it's interesting that a particular identifiable genotype points to this positive effect with this particular fruit. It seems to me that the relationship of PSADT to all cause mortality has not been studied yet in enough depth. And a corollary(which you point out), if a naturally derived substance with no discernible side effects can lower PSADT, how significant is this in the larger picture of PCa progression.

[Tall_Allen in reply to FRTHBST]

I hope patients won't go out looking to see if they have this mutation. Whether they do or not, eating highly colored fruits and vegetables is good dietary advice.

[Graham49 in reply to Tall_Allen]

Except that if you have the ala/ala genotype you might want to consider taking supplements since it appears that the psa doubling time effect might be dose dependent.

"High-dose Ala/Ala patients experienced a 10.3-month median increase in PSADT (P 1⁄4 0.11) while low-dose patients experienced a 2.8-month median increase in PSADT (P 1⁄4 0.08)."

[Tall_Allen in reply to Graham49]

They didn't control for diet. There is no reason to believe that intake of a variety of highly colored fruits and vegetables doesn't accomplish more because of improved bioavailability. This is what was found in lycopene trials - that high dose lycopene supplements didn't hold a candle to food sources (like tomato sauce) in generating high plasma levels. There are often enzymes, available in foods but not pills, that are necessary for absorption. Also, our microbiome co-evolved with us over millions of years to efficiently extract active ingredients from the foods we eat. It is almost always a bad idea to circumvent our biochemical processes.

[FRTHBST in reply to Tall_Allen]

I would never argue against eating the whole fruit or vegetable. Before diagnosis, I had a varied diet, lots of fruits and vegetables. I was healthy, except for the cancer. Clearly not everyone gets cancer, the basic process of disease initiation and progression has yet to be defined. It might be that the mechanism of immune response is interfered with or that the number of insults to the immune system become greater than it can deal with. It may be that our microbiomes are impacted by dietary or other relatively fast(in evolutionary terms) moving shifts brought on by modern lifestyle changes. Perhaps all of the above or something else affects intercellular organization through the extracellular matrix. We just don't have the answers yet.

We do have a library of phytochemicals naturally produced by plants that interfere with the cellular abnormalities associated with cancer. If we can identify specific genetic markers that tell us who might benefit from one versus another, perhaps we can begin to tease out relevant avenues for further research in this highly complex and promising area of research. In the case of muscadine grape skin extract, it may be similar to what's been found with the research on Turkey Tail mushrooms, that dried preparations retain bioavailability and in a concentrated form, raise plasma levels of the polysacharides and lipids suspected to be relevant- again, we just don't yet know.

I have read many of your posts and am impressed with your dedication to promulgating solid information as well as your deep knowledge of the subject and your generous effort to share such. A heartfelt thanks!

[Tall_Allen in reply to FRTHBST]

My friend took Turkey Tail mushrooms. He died in 6 months of metastatic diagnosis. Would it have been 3 months without it - who knows?

[Hidden in reply to Tall_Allen]

Did he get any proven treatments?

[Tall_Allen in reply to Hidden]

Oh yes! Pretty much threw the book at it. His oncologist was also willing to go with out-of-the-box stuff. Met with 3 top oncologists, plus his oncologist had weekly conference call with others around the world. But he had an undifferentiated type (low PSA, low AR) that just tore through him. His liver was affected early and that precluded some of the more toxic things.

[FRTHBST in reply to Tall_Allen]

Wow, so sorry to hear that. I was going to say in response to the use of Turkey Tail, that the supplemental treatments are just that at this point, best used as adjuvants. Even Paul Stamets' mother's remission from breast cancer was using TT in the context of Taxol and Herceptin treatment. Her prognosis with just the chemotherapy wasn't promising and the mushrooms may have made the difference. Really hard to know. Isolated one off results remain singularities, difficult to evaluate until we know more about the underlying processes. Most remissions I've read about involve prior or concurrent standard of care treatment along with the alternatives.

Again, sorry about your friend, having had some time to consider treatment options, most of my fear and anxiety was compressed into those first few months after diagnosis. I can imagine seeing the wall come up so fast must have been hard.

[Ribotom]

The subgroup for whom such supplements might be useful have the SOD2 Ala/Ala SNP.

The only reason I bring this up is that some of us might be able to access their allele status already, without buying an additional test, if you have had SNP testing done already. I was able to access my raw data from the company I used 11 years ago (23andme), which revealed me as Ala/Val.

If others have such data already and need advice on how to look up their raw data, I can advise.

[kapakahi in reply to Ribotom]

I've done 23andme - so how do I access the raw data? Once I get to it, I guess I'd do a find for...???

[Ribotom in reply to kapakahi]

So, first a couple of caveats:

I'm not trying to encourage or advertise for 23andme, or any other company that does SNP analysis. I am just saying that I happen to have had a 23andme test long ago, in 2009, and the chip they used back then seems to have included the SNP rs4880 for SOD2. Second, for people that have had an SNP analysis done more recently, I can't tell you for sure whether you'll have the rs4880 data or not in your raw data. I think people who bought from 23andme more recently may have had to choose whether to get health data, ancestry data, or both. Presumably the rs4880 SNP data would only be available as part of the health package, but I'm not sure about that.

Caveats aside, it's easy to check for the data:

(1) Log in to 23andme

(2) Go to the dropdown at the upper-right hand corner of the first page you see after logging in and select "Browse raw data"

(3) In the search box titled "Search for a specific gene or marker", type

rs4480

and click on the search icon.

You should see a search result for SOD2 and rs4880 at the bottom of the screen, including your genotype, which should be one of A/A, A/G. or G/G. These correspond to Val/Val, Val/Ala, or Ala/Ala, respectively. Supposedly the 25% of the population with the Ala/Ala genotype might benefit more from antioxidant supplements.

That said, I agree with Allen's comment that we *all* should just eat more colored fruit and vegetables!

[kapakahi in reply to Ribotom]

Mine says G/G under Your Genotype and A or G under Variants. I don't see where you got the Val/Val etc. to match with the A/A etc.

You said that G/G corresponds to Ala/Ala. Shouldn't A/A correspond to Ala/Ala? Is this just scientists trying to confuse me? (they don't have to try that hard [;-}

How you get from Ala/Ala to G/G is a mystery; I just don't see anything that matches what you cited: "...A/A, A/G. or G/G. These correspond to Val/Val, Val/Ala, or Ala/Ala, respectively." From what you and Tall Allen said, I'd think the people who are A/A are the ones who would benefit from this antioxidant.

I would benefit from a super high-dose antioxidant that makes me less confused.

I do recall taking SOD supplements many years ago, thinking it could help prevent cancer in me. It didn't. At that time I was eating papayas and mangoes galore along with all kinds of other exotic colorful fruit.

,

[Ribotom in reply to kapakahi]

It's a little complicated so ignore the details if you get lost. Here goes:

We have two copies of most genes. That's why you see Ala/Ala, or Ala/Val, or Val/Val for this particular position in the SOD2 protein: the first position (XXX) in XXX/YYY tells you what you have for the first copy of the gene, and the second position (YYY) tells you what you have for the second copy of the gene. So if you're Ala/Ala, all of your SOD2 protein has alanine (Ala) at that particular position. If you're Ala/Val, then you have some SOD2 protein with Ala at that position, and some SOD2 protein with valine (Val) at that position.

Each copy of a gene exists as two interacting pieces or "strands" of DNA. DNA is a double helix, and the "double" refers to the number of strands. So the first copy of the SOD2 gene exists as a segment of double-stranded DNA, and the second copy exists as a completely distinct segment of double-stranded DNA.

Each DNA strand is a long polymer consisting of a sequence of A, G, C, and T residues, like beads on a string. For each SOD2 gene, just one strand contains the information needed to make the SOD2 protein. This is called the "coding" or "sense" strand. The other strand is called the "antisense" strand. You can derive the sequence of the antisense strand from the sense strand easily, just rules of complementarity (A on one strand means there's a T on the other strand, and G on one strand means there's a C on the other strand) and by the fact that the two strands have opposite orientations (they pair up head-to-tail).

The rs4880 single-nucleotide polymorphism (SNP) means that some people have Ala at this position, and some have Val. The sense strand for Ala in this case has GCG, and the sense strand for Val is GTG. So now you should be able to see that if the middle position (of GCG) changes from C to T (GTG), that will change an Ala to a Val.

One annoying little wrinkle: the 23andme guys report the antisense rather than the sense nucleotide. So instead of reporting the sense strand sequence --for example, that you have the C/C genotype, which would mean GCG / GCG or Ala/Ala -- they instead report the antisense sequence, which would be in this same example G/G genotype (because C pairs with G, remember). So G/G means Ala/Ala. Similarly, if 23andme says you're A/G, that would be T/C for the sense strand, which means GTG/GCG or Val/Ala.

I doubt everyone is still with me, but that's how it works!

[kapakahi in reply to Ribotom]

arrrgghhh! (pulling wads of hair out of scalp) My report uses "missense," which sounds like it could be the same as antisense.

I wasn't aware that we had a geneticist on the forum...I can see why you use "Ribo-" in your online name. I can also see that the terms used - like A, G, C, T - are designed to weed out people with dyslexia, because dyslexia could be a slight impediment in genetic research. I mean, can you imagine the results you might get? Your reputation as an expert witness in death penalty cases? It took me years to be able remember the letter sequence for those wall outlets that prevent short circuits - you know, FGIC...no wait, CGFI...um...GIFC? CFGI?

Thanks for this explanation - I will try to figure it out - it's good for my shrinking brain.

[TheTopBanana]

How do you check for SOD2 Ala/Ala SNP? Is it blood test?

[monte1111]

Never met a wino who died of prostate cancer. Being run over by a garbage truck was high on the list.

[j-o-h-n in reply to monte1111]

City or Private truck(s)?

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 08/02/2020 7:29 PM DST

[j-o-h-n]

Greetings FORTHBEST, Here goes my spiel: Would you be kind enough to give us your bio? Age? Location? scores psa/gleason? Treatment(s) to date? Treatment center(s)? Doctor's Name(s)? Thank you!!! All info is voluntary but helps us to help you and helps us too.

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 08/02/2020 7:27 PM DST

[FRTHBST]

I am 64, was diagnosed in October of 2018 with Gleason 7(4+3) here in Santa Fe, NM. Original diagnosis by Dr. Eric Anderson at Christus St. Vincent Urology Associates. Since have consulted with Dr. Rixe (MO) and Dr. Jackson(Radiologist) at Christus St Vincent Cancer Center. I had a biopsy followed by bone scan and MRI. Bone scan negative for metastases, however MRI showed large tumor at periphery of gland with extra capsular extension. Was evaluated at Cleveland Clinic by Dr. Eric Klein, then by an MO, Surgeon and Radiologist at Sloan Kettering, Dr. Koutcher and Dr. Eastman, Dr. Kollmeier. I also visited MD Anderson for a consult on possible inclusion in a trial using Apalutamide prior to surgery(was not accepted). All of the physicians predicted major side effects with both surgery and radiation due to tumor size and location.

MD Anderson's pathology department upgraded my Gleason to a 9 and SK added the detail of Intraductal. After putting my data into the SK nomogram and the Johns Hopkins questionaire,(as well as my own continual reading) it seemed likely that whichever way I chose to go, chance of BCR was high, in the 70% range within 5 years. I elected to continue the supplement, diet and re-purposed drug regimen I had begun soon after diagnosis and do my own version of watch and wait which involved monthly PSA's and an MRI every 3 months. Last September I gave myself until an MRI in January to make a decision on definitive treatment. When that MRI showed increased tumor growth, I reviewed all the options. Going back over all of my research of the past 18 months a newer treatment caught my interest, IRE. My GP had been out to dinner with a colleague who's father was also a doctor. Dr. Gary Onik is a brilliant surgeon, something of an iconoclast and had been present at the invention of IRE out at Berkeley in the mid 2000's. I spoke to him and resolved to pursue this avenue. Unlike radiation or other localized therapy soft tissue damage is limited. Just when I had made a treatment decision,the pandemic intervened adding layers of complication.

Suffice it to say, I got a PMSA scan last month at UCLA, some activity beyond prostate in local area. On the 15th I will travel to Germany and have IRE combined with what they term ECT(electro chemical treatment not to be confused with ECT here which is electro convulsive therapy). My hope is that the non thermal ablation of primary tumor will set me up for some years before further therapy. The other options of radiation and various chemo interventions will still be on the table