Note: "p16 (also known as p16INK4a ...), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor." [2]
Note: Ki-67 "is a nuclear protein that is associated with cellular proliferation." [3]
Note: therefore "p16INK4A positive and Ki-67 negative" cells are senescent.
"Local tumor invasion is a critical factor for the outcome of men with prostate cancer. In particular seminal vesicle invasion (SVI) has been reported to be associated with a more unfavorable prognosis."
"The prognostic impact of local tumor progression was ascertained in over 1,000 men with prostate cancer."
"We confirm the notion that patients with SVI have a more unfavorable prognosis than patients with extraprostatic extension alone.
" Surprisingly, we found that the tumor invasion front frequently harbors p16INK4A positive and Ki-67 negative i.e., senescent, tumor cells.
"While the intraprostatic tumor periphery was a hotspot for both proliferation and expression of p16INK4A, the area of SVI showed less proliferative activity but was at the same time a hotspot of cells with increased nuclear p16INK4A expression.
" Senescence was associated with an accelerated migration of prostate cancer cells in vitro."
"This proof-of-concept study shows that invading prostate cancer cells frequently show signs of cellular senescence. This finding may open new avenues for neoadjuvant and adjuvant treatment concepts in men with locally advanced prostate cancer."
{I had cancer in a seminal vesicle, but was never informed of how this might affect survival.}
Can't understand it. If the SVI tumour front is less proliferative due to the higher expression of p16 and reduced Ki-67, how does the inferior prognosis can be justified. Or does the paper only aims at pointing out this contradiction?
The presence of senescent cells seems to have been a surprise to the researchers. The paradox is that such cells may accelerate migration. Which presumably accounts for the poorer prognosis.
There have been posts on the subject on how not to activate senescent cells, but we now have access to senolytic products - particularly fisetin. Seems prudent to use them from diagnosis.
I suppose Patrick, if I understand correctly the last sentence of the article, it was fortunate that the SOC (2015) when my husband had both SVI and extraprostatic extension was adjunct radiation six weeks after RP. His unfortunately was delayed for six months due to infection but still worthwhile it would seem.
I had delayed salvage radiation too. The surgeon felt that the prostate bed was "clean", and was concerned about the morbidity of radiation. But that would mean that I would have to be on ADT at some point. So I felt that salvage radiation, while aggressive & maybe inadequate, was the way to go. Unfortunately, the PSA, which dipped a little, was back up to the pre-radiation level at the next test. At this point, I have no regrets.
No we've felt the same Patrick. Although Ron's radiation which was due to start 8 weeks after prostate removal was delayed, due to infection from operation going to his pelvic bones we've always thought he was fortunate he did have it as it wasn't until three years later that the extensive bone and lymph node mets showed up and he commenced ADT. Think if he hadn't of had that radiation things might have been much worse. Even the radiation cystitis was worth it I think.
As for regrets...there have been some things I wish I'd been a bit more on the ball about...like when his mets first showed up and he was considered (unsuccessfully) for a trial. The specialist, a professor (at a different hospital to where we go) in his report recommended Lupron + Abi which wasn't SOC here at the time (probably still isn't) but when we went back to our urologist he dismissed it as overkill. I knew at the time we should have been more insistent but it would have meant going to a different specialist and that needed to be a joint decision. Maybe if he'd had double therapy at that time he would have had a longer run before becoming CR.
As time goes by, like you say you learn there's no point in having regrets. I've toughened up a bit now though, and will be a bit more insistent if I think there might be a better course of action.
When Abi & Enza appeared, I had to pause & rethink my strategy. But nothing had really changed. Neither offered cures. The temptation to hit it early & hard doesn't make sense with a treatment that is essentially paliative, imo.
Combined with ADT, you get a little more time before resistance. That makes it seem like a no-brainer, but the adaptations in response to Abi, say, create a cancer cell that is harder to manage than cells that have adapted to ADT alone.
What really matters is overall survival, imo***. It seems some get a survival advantage & some do not. I recall one paper that reported that those with Gleason pattern 5 (not Gleason score) might have improved survival. Maybe there are other clues as to those expected to benefit. I wouldn't want the expense & side effects of a therapy that gave me little added survival.
Years ago, my doctor noted that his patients on Abi had an easier time than those on Enza, but when Abi failed, the cancer really took off.
Was Lupron + Abi a good fit for Ron? Who can say?
I guess that someone will now point me to the definitive study, but I'm reserving Abi/Enza for when I need paliation. Meanwhile, I rely on periodic testosterone to shock cells that are adapting to low testosterone. It's like hitting reset.
Best, -Patrick
*** Some might dispute "What really matters is overall survival". A well-known person not on FPC once said, in response to me pointing out that a particular therapy offered no all-cause mortality benefit, pointed out that it did reduced PCa mortality. That came with the burden of added cardio-mortality. Supposedly an easier death.
Interesting insights Patrick and most appreciated.
Perhaps if Ron had stared on Abi with Lupron in 2019 the expected time to resistance (17 or so months) might have been extended...who knows.
What exactly is a Gleason pattern...do you mean samples that are 5+4 not the other way around or something to do with the mean of the samples? I haven't heard that expression before.
The way I think of it is that the choices, in relation to OS seem relatively straightforward if you are happy with /or have little knowledge beyond the trajectory of SOC. They become more complex once you know, that with all treatments presently available, for the majority at least, failure at some stage is going to be the outcome...and then you really need to be prepared to challenge the status quo...albeit with more than a little knowledge and support from those who are well informed and on the same page like yourself and similar others who post here .
Ron's experience with eight months of totally debilitating side effects, once he started Enza, was a lesson learnt that OS can come at too high a cost. The change to Abi + P has been nothing short of a small 'miracle'...providing a QOL that he hasn't experienced since pre lupron days. The MO says he'd expect, for Ron, it should provide a 2 year benefit but I know that's an arbitrary figure. A bonus is that Ron would never think of these treatments as palliative, is fairly pragmatic about the situation and feels he's doing very well.
Anyway nice chatting and learning a bit more about this condition. My best wishes for a Happy Easter. Marnie
Ramp7, you are another positive BAT story. Damn, we need to unite you Early Explorers, and learn from you. I hope you all compare notes and progress.
When I listen to Patrick, Paul, Russ, you all have your own approaches. You all modify for your specific belief. Power of the mind to buy in is key in my opinion. It is like we should have a semi-annual meeting to compare notes. All of you appear to be less rigid than the previous Trial work.
. I recently went to a new Oncologist hoping for BAT, but he said no. Too dangerous. My numbers too good right now. He said we will use BAT, when all else fails, as a last resort. This sounds like everything before it, which we later learn that “EARLY IS BETTER”.
At the moment my approach is pretty conservative. I met with Denmeade in Jan. and he basically said a high Testosterone / low Testosterone (Cycle) with Lupron in the background would work fine. My cancer was low burden with PSA increasing after completing the LuPSMA177 Trial at Dana Farber. My form of Testosterone is propionate which has a short half life. This one factor may be a big consideration. With a steep curve in the half life, cancer is stressed to this new environment at a fast rate. Cypionate is a much slower decay rate. Propionate requires frequent regular injections during the high cycle. Like with an insulin needle, don't even feel it. To date I'm a 50% responder with BAT. Just started my third cycle. I keep all three of my MO's up to date on my progress along with my Urologist. It's all documented on an easy to read pdf. And they all comment how pleased they are that I am responding favorably.
I had right side SVI and just happened to find the ASCO/AUA ~"Patients/Physician's Guide to Radiation Therapy after Radical Prostatectomy" shortly after my 2013 RALP. It had just been updated and basically ID'd four pathological findings that suggested advanced disease/progression. (Outside of Gleason, etc.) 1. Non-organ confined, 2. Ex-cap extension, 3. SVi, and 4. lymph node involvement. I was positive for the first 3 (5 lymph nodes were negative for PCa and positive for cancer #2, CLL, so, more accurately, maybe I was 3.5 out of 4). I was somewhat surprised at the finding that SVI was predictive of a more aggressive disease than was lymph node involvement. SWOG 8794 (circa 1988-97) was one of the first trials to look specifically at SVI effect on progression and OS. Your paper may shed some light on why that would be.
I found the guideline about a week before my appointment with my surgeon to review the results of the final biopsy. I started our conversation by mentioning the ASC0/AUA document with something on the order of, " Well, doc, there seem to be four negative indications from a final biopsy - and based on the recommendations of the guidelines that RT is a reasonable consideration for each, with 3 of the 4 negatives, it seems RT is a no-brainer." He paused for a moment and replied, "I wouldn't disagree."
I advanced my 8 weeks of IMRT to less than the recommended 6 month wait for ED/incontinence improvement. There was some discussion about ADT, but I didn't push it and none was done. I later found out that only the prostate bed was radiated and the dosage was on the very low side at 62 gray. No doubt, if doing RT today, the recommendation would be for the bed to be expanded to include the pelvic lymph nodes, the dose boosted, and ADT added (at least short-term.) I would also make the argument today, that in my case, including the lymph nodes might be beneficial for clearing them of CLL.
My 6 and 12 week post surgery PSA labs were both 0.03, so the IMRT was adjuvant therapy vs salvage. I got about 2 1/2 years of "undetectable" disease, so it is unclear how much benefit I got from the RT. It definitely did not help with the incontinence, as several years later I had AUS surgery. (I have reason to think there were other reasons for my persistent incontinence, but that is a story for another time and place/post.)
Thanks for again providing some new insight into the nature of our common disease.
Thanks, Patrick. My own choice is to do a 3-day senolytic regimen about every 3 or 4 months to hopefully clear (reduce) burden of senescent stromal cells and senescent cancer cells. They make trouble and promote invasion and metastasis via SASP cells. (See my previous posts.)
My own regimen includes combining Dasatinib 100mg/day with Quercetin 1500mg/day and also increase Fisetin to 1000mg/day. 3 days only. My ongoing supplements ( daily) include 500mg Quercetin and 500mg Fisetin among others. Paul
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