Sooo....advil works for SOME melanoma patients?????

I first reported on the supposed benefits of NSAID's ability to decrease cancer risk in 2012:  NSAID's and risk of skin cancer

Then last year (with much pandemonium in various news outlets this year) it was published that NSAID's reduced the bad boys - myeloid derived suppressor cells (MDSCs) and made anti-PD1 work better. 

Here's one post from 2015:  An Aspirin a day keeps melanoma at bay

And another from 2016:  Celecoxib: The stuff that's in NSAID's work synergistically with anti-PD1

Then at ASCO, they poured cold water over the whole thing.  See the last article in this post:  ASCO 2016: NSAID's many not aide response to anti-PD1 after all! 

But now, there's this: 

Differential expression of cyclooxygenase-2 in metastatic melanoma affects progression free survival.  Panza, De Cicco, Ercolano, et al.  Oncotarget. 2016 Aug 1.

The possible correlation between cyclooxygenase-2 (COX-2) expression and disease progression in melanoma is still a matter of debate. Analysis of COX-2 expression in 45 lymph node melanoma metastases demonstrates a significant correlation between the percent of expression and progression free survival (PFS). A positive COX-2 expression ≥10% (COX-2high), as opposite to a positive expression ≤9% (COX-2low), translated into a striking significant reduction of PFS of about 3 years. The reduction in PFS correlated neither with BRAFV600E nor with NRASQ61 expression in the analyzed samples. This concept was reinforced by the finding that tumour development in COX-2-/- mice was almost blunted. Similarly, inhibition of COX-2 protein expression in human melanoma cell lines, by using siRNAs technology as well as selective inhibition of COX-2 activity by celecoxib, reduced cellular proliferation and invasiveness. In conclusion we show that COX-2high is a negative prognostic factor in metastatic melanoma. Our study also clarifies that the uncertainty about the role of COX-2 in metastatic malignant melanoma, found in the current relevant literature, is probably due to the fact that a threshold in COX-2 expression has to be reached in order to impact on cancer malignancy. Our findings suggest that COX-2 expression may become an useful diagnostic tool in defining melanoma malignancy as well as argue for a possible therapeutic use of NSAID as add on therapy in selected cases.

For what it's worth!!! - c

And then there's me....

I can't believe I've been writing this blog for over 6 years.  I can't believe that I've been dealing with melanoma for 13.  For those of you who do not know, (and for those of you who do...please skip ahead...this story doesn't change!!!) I was diagnosed with melanoma via a cutaneous primary on my right upper back (Clark level 4, 0.61mm) with a positive sentinel node to the right axilla in 2003, rendering me Stage IIIb.  I opted to have a complete lymphadenectomy of the axilla, and despite weird nerve things to the area, have never had to deal with lymphedema.  I had no other treatment, since I didn't (then or now) view interferon as one.  In 2007, (almost 5 years later) I had what was deemed a "second primary" to my left forearm (Clark level 3, 0.5mm) with no positive nodes, but still opted for what was basically a complete lymphadenectomy to my left axilla.  Still, as before, no other treatments were available.  In 2009, on a routine chest X-ray (scans were not really done back then), "something" was noted in the right upper lobe of my lung.  I was told by multiple experts, it "absolutely did NOT look like cancer".  After watching and waiting, with scans that showed no worsening nor improvement, a bronchoscopy and subsequent path report revealed: "Yep, melanoma can look exactly like that!"  Brain scans showed a 3mm met to the right frontal cortex.  On April 27, 2010 I had SRS to the brain met and on the 30th, a right upper lobectomy of my lung.  Not long after returning to work that August, (Yes, I was very lucky to be given time off to recoup and spend with my family!!!) I thought my throat felt really weird.  Understand, NONE of my mets had caused me one moment of pain, dizziness, shortness of breath - nothing.  The surgery and radiation to get rid of them - completely miserable.  But the melanoma itself - not a problem.  However, with the strange feeling in my throat....I take a look.  Yep, ugly looking black thing on my right posterior pharynx peeking out from behind the tonsilar pillar.  Off to the ENT I go and have my right tonsil with wide margins removed Saturday, October 30, 2010.  Path result is not surprisingly melanoma, with a 1.9cm X 0.7cm X 0.8cm tumor growing on a stalk attached to the right tonsil.  Dealing with Trick or Treaters was weird being unable to speak, B at work, and the kids off at college!!! But, I was back to work on Monday.

So....what was I doing while all this was going on???  Initially, just trying to make sure the kids still did their homework and got to go to dance and soccer practice as usual.  I worked hard to provide birthdays and play that were still the fun times all kids deserve, while occasionally wondering what the hell I was going to do if that shit got into something I couldn't cut off and whether I was insane to continue to pursue my NP and master's degree.  Once dealing with brain and lung mets....I was mostly just trying to survive the insults the treatments had been to my body, regain my strength, and keep the kids on an even keel as Rose was just graduating high school, then joining Fred in college.  In fact, I didn't even tell them about the tonsil met and surgery until it was over, an omission I got a great deal of grief for, while constantly wishing ipi would magically gain FDA approval.  Meanwhile, B was searching madly for a treatment or trial.  He was drawn to vaccines, though we turned one such option down at Vandy - and a good thing, too, as it was ended early when the patients getting vaccines did less well than those without!  The search was further complicated by the fact that between all my events, I was NED.  Available trials at the time (and it is barely any better now) required measureable disease.  There were strange discussions of allowing my next tumor to remain and grow, so that perhaps I could gain entry.  In December of 2010, a repeat brain scan showed a 4mm brain met to my right parietal.

Just prior to that scan, B had procured a visit with Dr. Weber in Tampa/Moffitt, to discuss my case and participation in an NED arm of a Phase 1 trial testing nivolumab combined with a peptide vaccine.  We made the trip Dec. 12, 2010.  The vaccines were what drew B's attention to the trial.  Little data was available about anti-PD1 - nivolumab/Opdivo - then known as MDX1106 and later as BMS936558.  In fact, here's a little story from 2013, that tells the history of the drug and my place in the trial:  Love Potion #9 

At our visit, there was much discussion of my past and future.  A review of my latest scans - Was that really a brain met?   If so, it would preclude my participation in the NED arm of the trial, yet not be sufficient tumor burden to allow my enrollment in the active disease arm. Here's how things went as I wrote at the time:

'Weber pops back in to tell us that he doesn't really know that it is a met at all. He is going to get the other folks to give their opinion.  On his return, he says that the other radiologist/neuro people couldn't definitively say that the lesion in question was a met. He tells us that to his mind, I have "minimal residual disease" and therefore qualify for his study should I wish to participate in it. I figure the conversation went something like this: 
Weber = Do you think this lesion is a met? 
Neuro/radiologist = Well, given her history, probably. 
Weber = Yes, but, on its own. Can you tell me that this is definitely a met? 
Neuro/radiologist = Well, not definitely.'

Weber dubbed my situation as one of being in "Melanoma Neverland"! Here's the post that tells the entire story of that visit: Melanoma Neverland  I agreed to participate in the trial.  [From that post] As Brent put it, "We are in Melanoma Neverland, but this may be a door out."   We rushed frantically to sign papers, complete an EKG, various labs and other madness...before catching our return flight to Atlanta.  I started the actual trial, as patient #9 (or possibly #3, if you discount those who dropped out) in the first cohort of the NED arm.  My dosage of nivo was only 1mg/kg.  The other cohorts were given 3mg/kg or 10mg/kg respectively, with an opposing arm of three cohorts with active melanoma being treated as well.  We were all given 6 peptide vaccine injections with our respective anti-PD1 infusions every 2 weeks for the first 6 months.  We were then given only an infusion of our dose of anti-PD1 every 3 months for the next 2 years.  The peptide vaccines were proven to provide no benefit whatsoever.  Here's a post from 2013:  Peptide vaccines do NOT trigger immune response to melanoma!  On the other hand, we ratties benefited a great deal from the nivo.  My brain ditzel was gone from my MRI by March, 2011.  Here are a couple of posts in which our trial results were reported:

From 2014 when results were first published:  Ces't moi! Results from the 33 ratties in my nivo study - published!
Also from 2014, my thoughts when looking back on my trial:  My Nivo/opdivo trial - First dose 4 years ago!

So, here I am today:
156 months (13 YEARS!!!!) post my original melanoma diagnosis in 2003 at age 39
76 months Stage IV (more than 6 years!!!)
70 months NED
68 months after starting nivo (Opdivo)
38 months (more than 3 years) since my last nivo infusion in June of 2013

I am now being seen and scanned annually.  Or at least that's what I am supposed to do!!!  Scans (a CT of neck, chest, abd and pelvis with an MRI of my brain) were scheduled for the 25th of this month.  BUT....what am I notified of by my dear, caring friends (who take my money!!!!) at Blue Cross Blue Shield?

You may experience the pleasure of your CT scans as planned, however in regard to the MRI...."Based on eviCore Oncology Imaging Guidelines, we are unable to approve the study your doctor requested.  Your records show that you have SKIN DISEASE that is stage 2B to stage 4.  Follow up magnetic resonance imaging, detailed picture study, of your brain is supported for this problem once per year for the first 5 years after your skin disease was found.  Your records do not show that this applies to you. This decision just means your health plan won't pay for the service.  You can still receive the service, but you will need to pay for it yourself.  {signed} Michele Awobuluyi, MD"

Skin disease?  Melanoma is not poison ivy or eczema!!!!  Seriously?!!  And just for the record....I have paid into Blue Cross MORE than they have EVER paid out for me!!!  Even with the treatments and surgeries I have had.  Yes...I did the math!!!  What a F@CKI#G A$$ and disappointment you are DOCTOR (????????????????) Awobuluyi!!!!  I operate under the principle that healthcare providers are supposed to PROVIDE healthcare!  Under what principles do you operate? Oh, that's right!  NONE.  Not the Hippocratic Oath nor basic common sense nor human empathy.

Oh, well.  I am in the process of appealing the "decision".  Just what I deserve to be spending my time doing while Michele Awobuluyi gets paid to check BCBS boxes in a cubicle somewhere.  I hope it is a really ugly navy cubicle, with lint and food stains on the rough Miller-Martin divider.  I hope it smells of rank oil and feet, and some poor soul is constantly hawking up loose, productive loogies just beyond the panel...but I doubt it.  I am more than aware that I am not alone. I work with our referral coordinator to make these appeals for my own patients all the time.  Many folks are much worse off than myself, having no insurance.  Having no comprehension of what all the letters and word salad you are sent as a patient even means.  Having no idea that they CAN appeal.  Having no ability nor the strength to do so!!!

On top of all that....the ludicrousness of the entire thought process behind the denial of an MRI with a patient having Stage IV melanoma, especially one with prior brain mets, boggles the mind!!!  When I wrote my post "There's a reason they're called melanoma WARRIORS!!!" I wasn't even thinking about this denial or melanoma progression data.  But, look at our sad histories!  We have fought and endured and lasted far longer than anybody ever thought we would.  Yet, so many of us have spent YEARS NED only to recur in the brain and elsewhere.  Not only that, for the most part, we were completely asymptomatic!!!  If you wait until you pass out and have a seizure...it is almost always too late!!!  Melanoma REQUIRES that we strike back - and hard! - sooner, rather than later.  Without scans...and in the brain that means an MRI...we have no way of knowing what is going on in there.  But, of course, the Queen of Melanoma, Rev Carol, already addressed this, years ago!  Here she is from 2014:

The NEED to DEMAND scans in melaland....from Rev. Carol Taylor's blog....attittude of grattitude

Excerpts, from our amazing Queen:  "I feel a very strong, stepped-up sense of urgency to press all my melahomies, no matter where along the staging spectrum they reside, to demand to be scanned.  ...  Prepare to be your own best advocate and prepare to push for what YOU need to stay on top of this disease and for YOUR peace of mind. You may have to push your doctor. You may have to get another doctor (make sure any doctor is a melanoma specialist and understand they will not all agree. Just because ONE doctor tells you something doesn't mean ALL doctors you see will tell you the exact same thing!) You may have to do battle with your insurance company. You may have to do battle with them every single time your doctor orders scans. OK. While this stinks and isn't how it should be, if this is how it is...do battle. And, if your doctor HAS ordered scans and they are denied, enlist your doctor's office to help you with your insurance company. They/the hospital should have someone on staff trained for this. Use them! ...  A word to doctors. I'm learning that some of you...not all of you, and for those who scan, I am truly grateful but you are few in number when it comes to scanning stage 2 melahomies and under...some of you...many of you refuse to scan my lower staged melahomies. You, of all people should have a basic understanding of this disease and how it works and that it has NO MO. None. Zilch. Nada. You know.  People with in situ (stage 0) melanoma can be stage 4 in a matter of months, years, or never. You know that the ONLY way to be sure of what melanoma is, or is not, doing is with a scan.  ...  Give my melahomey and your patient...this person who is trusting YOU with their LIFE this much, this peace of mind, this ray of hope.  ...  It is your job to help and do no harm. That's what you swore to do. Do your job. Do no harm. Help. Scan.  ...  And now, insurance companies. ...  I'm telling my melahomies to fight you tooth and nail if they have to, in order to get the scans their doctors order and that you all too often deny. Really now, all companies and corporate entities are made up of real-life, flesh and blood people. Get in touch with your inner humanity and stand with us instead of against us.  ...  It makes good business sense and will save you money in the long run to pay for our scans upfront. ...   It will be far cheaper to pay for scans NOW and catch much disease early, than to let it go unmonitored...  And...learn from our fellow cancer road travelers who have colon cancer. While melanoma is rising, colon cancer is on the decline! Hallelujah and praise the Lord! Why the 30% decrease in colon cancer rates, you may ask? Because more people than ever before are getting colonoscopies as a preventative measure and precancerous lesions are caught and removed EARLY! Polyps that are cancerous are caught and removed while they're tiny before they become huge problems.  ...  I'm hoping and praying that more and more of my fellow travelers on melanoma road will make themselves heard, will advocate for themselves and for their loved ones, and really start to demand proper treatment at all levels and that starts with demanding scanning.  ...  If more and more make those demands, more and more will see results.  But, we can only do so much. We can demand.  Will you hear?  Will you help?  Or will you harm and possibly kill?  Please. Stand with us.  We're counting on you.

Remember...one day YOU may hear that YOU'VE got melanoma or that your spouse or your child does or your parent or your sibling...then what?  Will you or they have to live with the same rule you've imposed on us? I strongly doubt it.  You'll get it then because you will have gotten it.

Make a difference NOW. Before that happens.  Thank you. I really Do want to rise up and call you 'blessed.'"

I told you! She is the Queen!!!  I will continue to fight.  I hope you do, too.  And if you can't fight for yourself.  Enlist others to help.  You can do this.  But, there are many of us here to help....should you ever have the need.  I'll keep you posted.  Love, c

There's a reason they're called melanoma WARRIORS!!!!!!!!!!!!!

Yes, we have the occasional navel watcher.  The one with a hangnail....who starts yelling:  "Oh, my goodness!!  I have some peeling skin at the edge of one finger!!  What does that mean?  Do I have melanoma/side effects/a brain tumor????"  And those, who have been through their own significant difficulties...but were fortunate enough to come out the other side...who when faced with their own misconduct shout, "I have PTSD!!!  What am I to do?"  So....to the first I might be inclined to answer...."Perhaps so (to the brain tumor) if you think it seems realistic to focus on a hangnail!"  And to the later..."Quit being an ass!  You're a lucky bug (compared to many)!  Get over yourself!!!"  Yeah, I know....I'm not a very nice or sympathetic person.  Hey!!!  Maybe melanoma made me that way!!!  Nah....It's all just me!!!

However, far more often I am struck by the deep caring nature and incredible strength the folks I've come to know and love with melanoma CONTINUALLY exhibit.  I first wrote about some of these souls in 2012:  Oh, the people you'll meet....  About Patti, 9TS, Alisa, Eric, and other beautiful lives in 2015:  Melanoma kills....the best people  About the amazing Brit, Lori Murdock, later that year:  Merde again!  And most recently, my ode to the dearest, sweetest, bravest man I never met.  Dear sweet Artie.  His 'handle' - arthurjedi007 - on MPIP said it all:  Artie: A beautiful soul, amazing knight

Despite a very rough week (months for others) for some of my amazing melanoma peeps, I have not heard one word of complaint.  Not one whine.  Some shock, some sadness. But mostly, an absolute determination to move forward in the best way they can and LIVE every minute.  Here are a few of their stories...  {A writer's note:  Should the details of the stories that follow have errors in order of findings or treatments...the error is all mine.  However, in my defense, I remind you ~ the stories these peeps share are NOT of their own problems and troubles.  THAT is NOT their focus...so piecing together the details of their melanoma journey was a bit of a challenge...even having known them for years.  I think that says a lot right there!!!}

To start the week with a good note...despite what had to be a harrowing build up...my brother-from-another-mother, Stevie...who has been dear to me since 2011....began his melanoma journey in 1994 with a cutaneous primary.  He developed a lung nodule, removed surgically, in 2011...joining me and others as Stage IV, yet NED, before the FDA approval of BRAFi, ipi, or anti-PD1.  He ended up doing IL2 that same year, with additional surgery to a nodule in his trachea. Five or so brain mets were zapped in 2014 and he began BRAF/MEK with a good response.  Three more brain mets zapped in 2015 and side effects to his BRAFi combo led to a break, a modified dosing schedule, and eventual basic stability of all bits and bobs with a switch to TAF/MEK.  In the months leading up to July he had been watching scans that were showing slow "growth" at the site of a previously zapped brain met and was making plans for a craniotomy to deal with the spot if scans continued to show growth.  Luckily, they did not.  Scans remained stable...so the process continues and he joins Dick K as an example of long term survivorship on BRAFi.  But all of that.....is not the important stuff.  The important stuff is that he is an amazing guy.  A great husband and dad, whose eldest is heading out to college this month, and two other young teens will be heading back to school very soon.  He is always supportive.  Gets me and makes me smile.  Puts up with my bossy attitude.  An awesome man.  A beautiful friend.

There's Bennie.  A big guy, with an even bigger smile from Texas.  Great dad of two young kids....just started building a house after completing an arm of my trial...Stage IV, NED, nivo/ipi.  Bennie was diagnosed with melanoma in 2005, but became Stage IV in 2013 with mets to lungs, liver, and hip.  After some surgery and IL2 and later, Zelboraf, became NED that September and was even able to go off meds as they were causing pretty miserable side effects.  But, in December of 2013 a brain met showed up on scans and had to be zapped.  Around that time, he and his wife found Moffitt and Weber.  Testing leading up to his trial participation was incredibly stressful as he had to be NED in order to qualify for the ipi/nivo combo offered.  They made it!!!!  I have never seen a pic of Bennie with anything less than a big smile on his face.  Yet, I know how difficult these past years must have been.  He had small children.  He had to take IPI AND nivo.  And he traveled to Tampa for 2 YEARS from his home in Texas...finishing his trial...still NED, in May of 2016.  However, this week, he got the results of his 3 month post trial scans.  Another brain met.  He is making plans for zappage and figuring out what to do next.

There is the ever beautiful, grace and humor filled, QUEEN of melanoma - Dear Reverend Carol Taylor.  She dealt with a cutaneous melanoma and positive nodes in 2008.  Removal of same left her with lymphedema for which she wore tattoo printed compression sleeves that got her some looks back in the day before everybody was tatted up, attention she parleyed into great teaching, sharing, and learning experiences.  She has spent years being the most amazing voice of advocacy.  Her posts from 2010 to 2015 on her letsgivethanks - an Attitude of Gratitude blog, along with her Melanoma Prayer Center, gave folks just what they needed from deep love and encouragement to a bit of a kick in the pants as required. After all those years as Stage 3b, in September of 2015, she progressed to Stage IV with mets to lungs, brain and sacrum.  After surgery to one brain met and radiation to the other three along with her spinal met, she started the ipi/nivo combo...whose side effects landed her in the hospital...twice.  With that option shot,  she started Zelboraf and was doing pretty well.  This June, scans revealed the development of a blood clot in the brain.  She has exited ever gracefully, stage left, from her position as reverend and her blog....yet her posts from her beautiful heart...remain there to inspire us all.

I am contacted by several new peeps a week with questions about treatment and melanoma.  When I am....I try to look at this blog with fresh eyes....wondering what it is folks see. I've told B and others that I mostly appear to be a crazy person.  I can see where there is some good info for folks...but I would walk away thinking..."That woman is nutters!!!"  B (and others) when told of my conclusion, had a moment where he looked as though he might argue...but...changed his mind!!!  I understand that.  We are honest with each other.  However, there are those in melanoma land who AREN'T nutters!  They are always calm, and wise, and measured in their outlook and response to others!!!!  Brian P is THAT guy.  Another man in the prime of life, with two young kids, has been working toward his goal of resuming his career as a pilot and buying a home ~ activities sidetracked by melanoma.  He was Stage 2 in 2006.  Drew the short straw and did interferon in an ipi vs interferon trial in 2011.  Mets to his intestine led to surgery in 2013.  Positive nodes in the abdomen led to participation in a sequential anti-PD1/ipi trial in 2013.  He had been stable for 2 years, 1 year off treatment, when just this week....routine scans showed positive nodes. Surprise, disappointment....certainly.  But, mostly...Brian just plows forward...seeking info from Dr. Weber (who actually provided some hopeful news, in that perhaps Brian may be dealing with an immunotherapy ditzel...along with a diatribe on the ineptitude of radiologists...been there, heard that....as well as some reasonable treatment options should they be needed) to determine what to do next.

And there's my sweet, dear Joshie!!!  ANOTHER young guy with a couple of kids and a great family.  He's honest and real...and sick and tired at times...just like the rest of us.  But, with a fighting spirit and voice of kindness to others of which there is no like. Initially diagnosed in 2011 with some recurrences at the original site....a scan in 2013 showed lung mets.  Ipi followed by IL2 was completed.  He remained NED until 2015 when progression occurred in his lung, liver and pancreas.  He attacked with ipi and surgery.  In between he had blood cells harvested for a cutting edge TIL's procedure followed by IL2 and ipi that he will be starting soon.  He admits to worry and confusion and desperation.  But shows us all how to move forward - in spite of EVERYTHING!

While by no means a comprehensive list, these are dear ones who have inspired me and touched my soul.  They are some of the best people this world has to offer.  The fact that they also have melanoma is just a 'BLECH!' on their day and of course, a great concern to those who love them. I want each of them to know how much their example means to me and many others.  I wish each of you ~ hope and peace and love....along with a treatment that kicks melanoma to the curb.  WARRIORS, indeed.  - love, c

Sew Chaotically! - Waste Not, Want Not #3

So....a zillion years ago, I got this pattern (Simplicity 5007) to make some summer play tops for Rosie.  Recently, while putting away scraps of material and thinking, "Why do I save these bits?!!"  I became inspired!!!

 And, NO!!!  There are some things this 52 year old girl will NOT be wearing.  (I'm not even sure Rosie will!!!) but I had fun messing around and playing with my serger!!!

You may remember from my Paris Shirt Dress!!! that I loved the reversibility of the fabric and had been tempted to use it that way, somehow, in that dress.  Well, I didn't...but had fun doing so in this little elastic waist skirt.

I thought it turned out pretty cute.  Just an easy little skirt for summer.  Hee hee!!!  Sew (and play!) Chaotically!!! - c

Everything cures melanoma...redux....#5?????

Lord knows I have covered 'most' everything that folks have tested and came away saying would cure melanoma:  coffee, curcumin, strawberry extract, wine, doxycycline, beta blockers, snake venom, shitakes, eggplant, potatoes, tomatoes, cimetadine, NSAID's, Vitamin D, Vietnamese Sophora root, exercise, sandalwood...I did leave off sea urchin snot....just seemed a bridge too far!!!!  Here are those posts if you'd like to see the data for yourself:

From 2013:  Everything cures melanoma, so why do we have it?

Be Better in 2013: Jump up, jump around and get down!

2014: Red, red wine boosts radiation effect

Also from 2014:  For melanoma: eat that curry again we just don't know why!

2015: Everything kills melanoma: Take 4

Now we have these reports touting the benefits of dill and parsley, coffee and curcumin again, anti-cholesterol meds and stress control! Here you go:

Efficient Synthesis of Glaziovianin A Isoflavone Series from Dill and Parsley Extracts and Their in Vitro/in Vivo Antimitotic Activity.  Semenov, Tsyganov, Semenova, et al.  J Nat Prod. 2016 Apr 21. 

A concise six-step protocol for the synthesis of isoflavone glaziovianin A (GVA) and its alkoxyphenyl derivatives 9 starting with readily available plant metabolites from dill and parsley seeds was developed. The reaction sequence involved an efficient conversion of the key intermediate epoxides 7 into the respective β-ketoaldehydes 8 followed by their Cu(I)-mediated cyclization into the target series 9. The biological activity of GVA and its derivatives was evaluated using a panel of seven human cancer cell lines and an in vivo sea urchin embryo assay. Both screening platforms confirmed the antimitotic effect of the parent GVA (9cg) and its alkoxy derivatives. Structure-activity relationship studies suggested that compounds 9cd and 9cf substituted with trimethoxy- and dillapiol-derived B-rings, respectively, were less active than the parent 9cg. Of the evaluated human cancer cell lines, the A375 melanoma cell line was the most sensitive to the tested molecules. Notably, the target compounds were not cytotoxic against human peripheral blood mononuclear cells up to 10 μM concentration. Phenotypic readouts from the sea urchin assay unequivocally suggest a direct microtubule-destabilizing effect of isoflavones 9cg, 9cd, and 9cf.

Higher Caffeinated Coffee Intake Is Associated with Reduced Malignant Melanoma Risk:  A Meta-analysis study.  Liu, Shen, Shi, Cai, PLoS One.  2016 Jan 27.

Several epidemiological studies have determined the associations between coffee intake level and skin cancer risk; however, the results were not yet conclusive. Herein, we conducted a systematic review and meta-analysis of the cohort and case-control studies for the association between coffee intake level and malignant melanoma (MM) risk.  Studies were identified through searching the PubMed and MEDLINE databases (to November, 2015). Study-specific risk estimates were pooled under the random-effects model.  Two case-control studies (846 MM patients and 843 controls) and five cohort studies (including 844,246 participants and 5,737 MM cases) were identified. For caffeinated coffee, the pooled relative risk (RR) of MM was 0.81 for those with highest versus lowest quantity of intake. In the dose-response analysis, the RR of MM was 0.955 for per 1 cup/day increment of caffeinated coffee consumption and linearity dose-response association was found. Strikingly, no significant association was found between the decaffeinated coffee intake level and MM risk.  This meta-analysis suggested that caffeinated coffee might have chemo-preventive effects against MM but not decaffeinated coffee. However, larger prospective studies and the intervention studies are warranted to confirm these findings.


Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism.  Yang, Bai, Xiong, et al.  Nature. 2016 Mar 16. 

CD8⁺ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8⁺ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8⁺ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8⁺ but not CD4⁺ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8⁺ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8⁺ T cells were better than wild-type CD8⁺ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Curcumin:  A new candidate for melanoma therapy?  Mirzaei, Naseri, Reazee, et al.  Int J Can.  2016 Jun 9.  

Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic, and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g. BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin.

Association of stress coping strategies with immunological parameters in Melanoma Patients.  Trapp, Trapp, Avian, et al.  Acta Derm Venereol. 2016 Jun 9.

In this exploratory case control study the association between stress coping strategies and lymphocyte subpopulations was calculated in 18 non-metastatic melanoma patients and 18 controls with benign skin diseases. Coping strategies were assessed using the German version of the stress-coping questionnaire (SVF 120). While in the control group patients showed significant negative correlations of lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, CD45+ cells) with coping strategies that refer to defence, in melanoma patients significant positive correlations between lymphocyte subpopulations (CD3+, CD4+, CD19+, CD45+ cells) were found with regard to coping strategies that are characterized by diversion from stress and focusing on stress-compensating situations. The present data, in melanoma patients and controls, show contrary correlations between stress coping strategies and lymphocyte subpopulations. The interconnection between stress coping and immunologic alterations in malignant melanoma is a field deserving further multiprofessional investigation in order to provide new therapeutical approaches in the treatment and understanding of melanoma patients.

Supercritical Fluid Extract of Spent Coffee Grounds Attenuates Melanogenesis through Downregulation of the PKA, PI3K/Akt, and MAPK Signaling Pathways.  Huang, Wei, Siao, et al.  Evid Based Complement Alternat Med. June 2016.

The mode of action of spent coffee grounds supercritical fluid CO2 extract (SFE) in melanogenesis has never been reported. In the study, the spent coffee grounds were extracted by the supercritical fluid CO2 extraction method; the chemical constituents of the SFE were investigated by gas chromatography-mass spectrometry (GC-MS). The effects of the SFE and its major fatty acid components on melanogenesis were evaluated by mushroom tyrosinase activity assay and determination of intracellular tyrosinase activity and melanin content. The expression level of melanogenesis-related proteins was analyzed by western blotting assay. The results revealed that the SFE of spent coffee grounds (1-10 mg/mL) and its major fatty acids such as linoleic acid and oleic acid (6.25-50 μM) effectively suppressed melanogenesis in the B16F10 murine melanoma cells. Furthermore, the SFE decreased the expression of melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). The SFE also decreased the protein expression levels of p-JNK, p-p38, p-ERK, and p-CREB. Our results revealed that the SFE of spent coffee grounds attenuated melanogenesis in B16F10 cells by downregulation of protein kinase A (PKA), phosphatidylinositol-3-kinase (PI3K/Akt), and mitogen-activated protein kinases (MAPK) signaling pathways, which may be due to linoleic acid and oleic acid.
 
While most of these...coffee, curcumin, and becoming a bit more zen most certainly....are likely to do no harm, do keep this word of warning in mind should you be determine to cure yourself:   Combining alternative and conventional treatments can be a risky business!

For what it's worth! - c

Paddle Boarding!!!!....

....as you do....when you turn 52!!!!!!!!!!!!!!!!!!!!!

Like a boss!!  Hee hee!!!

Soooo much fun!

 

Not so long ago, there were times when I thought I would never see this day.  Thanks to all of you who see me through and make all my days special.  And of course, there was this...

I wish you peace, and birthdays, and good fun, and those who love you.....but most of all ~ hope....on dragon fly wings.   les