Monday, November 30, 2015

Response to Jenny regarding adjuvant treatment options as StageIIIB:

Since in it's wisdom the Mollom software blocked my response to your post on MPIP, with questions about being a Stage IIIb melanoma patient with two recurrences and adjuvant treatment options from ipi to leukine (GM-CSF), to anti-PD1 - perhaps I can fix it so that you can see it here:

Hi Jenny,

Melanoma treatment decisions are never easy and are particularly murky for folks who are looking for an adjuvant therapy.  There are many posts on ipi as adjuvant here...including several testimonies that folks have in fact received and docs are prescribing ipi at 3mg/kg rather than the FDA approved 10mg/kg as adjuvant.  As both are on the have latitude...though payor coverage is certainly an issue.  Here's a post with an article with data re: NED folks who took ipi:

As far as GM-CSF or leukine:  Here is a post with some data that you may or may not have found:

In this webinar, Weber and Agarwala note that when ipi is COMBINED with GM-CSF "1 year survival = 68% vs 52% in patients given ipi alone."  However, I think that was from a study in patients with disease, rather than NED, but here's the link:

And, yes...there is data out there about anti-PD1 as adjuvant.  I was rendered NED via surgery and SRS to lung and brain mets in 2010 and participated in the NED arm of a Nivo/Opdivo trial.  Despite some heartbreaking losses, my fellow ratties and I are doing much better than our predicted shelf life.  I remain NED today.  Here is a published report of our data:
With the main points being:  As of 2014, my ratties and I had  an average "relapse free survival of 47.1 months" while "prior studies demonstrate 12 months as a reasonable benchmark".  And....we continue to survive.  So....  Hopefully, with its higher response rate and lower rate of side effects...anti-PD1 products (nivo/opivo and pembro/keytruda) will be approved as adjuvant therapy soon.  However, Big Pharma and the FDA move in mysterious ways and finding anti-PD1 NED trials currently is difficult if not impossible.

Pavlick is amazing and well respected.  Were I in your shoes, I would discuss these options with her and certainly give respect to her advice.  Hope this helps.  I wish you my best.  Celeste

Overcoming resistance to BRAFi in melanoma with the addition of Mcl-1 inhibitors?

For those with BRAF positive melanoma tumors....BRAFi, especially when combined with MEKi, can provide amazing responses.  And while that combo, along with lessons learned in administration techniques, is allowing many to continue to respond longer, diminished response over time remains a problem for some.  Here is a post that addressed that:  BRAFi: What predicts resistance?
Here is an article with another theory/approach:

Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma.  Oncotarget.  Fofaria, Frederick, Sullivan, et al.  2015 Oct.

Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment.  Here, we establish a mechanism of resistance and subsequently identified a suitable drug combination to overcome resistance.  Single treatment of BRAF mutant melanoma cell lines with vemufaenib or dabrafenib (BRAFi's) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1.  [This in turn completely blocked BRAF and MEK inhibitors from killing melanoma cells.]  Melanoma cells resistant to BRAF inhibitors showed massive expression of Mcl-1 as compared to respective sensitive cells.  Silencing of Mcl-1 using siRNA completely sensitized resistant melanoma cells to growth suppression and induction of apoptosis by BRAFi [the BRAFi could stop growth and kill the melanoma cells once again!].  In vivo, vemurafenib resistant...[cells were implanted in mice]...and...showed substantial tumor growth inhibition when treated with a combination of vemurafenib and Mcl-1 inhibitor or siRNA.  [Analysis showed] enhanced expression of Mcl-1... in vemurafenib resistant tumors [but] levels of Mcl-1 ... was diminished in the tumors of the mice treated with either of the combination.  Biopsied tumors from the patients treated with or resistant to BRAFi revealed overexpression of Mcl-1.  Results suggest that combining BRAFi with Mcl-1 inhibitors may have ... an advantage to melanoma patients with acquired resistance to BRAFi alone or in combination with MEKi. mice and men....folks with BRAF positive melanoma tumors who develop resistance to BRAFi or BRAFi combined with MEKi then have tumors that show excessive production of Mcl-1.  When the mice with this problem were given vemurafenib combined with a Mcl-1 inhibitor or siRNA...their tumors no longer had the overexpression of Mcl-1 and theory....again respond to BRAFi.  This would be super cool if it works in peeps.  Time will tell.  Hang in there, ratties!!!  - c

Saturday, November 28, 2015

Sew Chaotically! - A line skirt (M3341) and Morris Blazer "vest"

A no-fail a line skirt pattern.

This material is soft as fleece, 100% cotton that washes up beautifully and looks like a rich wool!  Picked it up at Jo-Ann's.

Feeling ok about my pattern matching...

It's not perfect...but, in my defense the material was stretched a little wonky in one area.  The combo, though I doubt she will wear them this way!!!

I used remnants of purple fabric from a previous dress and the left-overs from this skirt to create a Morris vest!!!  Here's some info about Morris they should be:  Spring summer sewing: Lissette passport and Grainline's Morris blazers

Seam binding was used to finish the arm holes.  Have to say it turned out pretty cute!  Sew chaotically!! - c

Wednesday, November 25, 2015

Nivo/Opdivo approved as first line for melanoma!

Nivolumab/Opdivo (the drug I took in my trial) has gained FDA approval for use as a single agent, front line treatment for BRAF V600 wild type, unresectable or metastatic melanoma according to announcements put out today! FDA approves frontline opdivo for advanced melanoma
And here: FDA Approval of Opdivo in BRAF V600 WT Melanoma

Have to say, I don't like the limitation based on BRAF status...since we already know that such status doesn't matter in terms of a response to anti-PD1:  Nivo/Opdivo effective no matter BRAF status
The restriction in today's announcement is based on the way the data was attained from the study used to gain this approval, the CheckMate 066 trial.  (The narrow way in which trials are used when drug companies gain approval from the FDA is a HUGE problem.  Human brains are not so narrow as to only be able to interpret data in specific, grouped sets! We really are capable of putting two and two together and while Opdivo proved effective in the wild type ratties in the 066 study, we have simultaneously learned that other ratties respond as well.  Tunnel vision is NOT required!) But, this approval gives one more option for lots of melanoma peeps and as more and more Opdivo approvals are gained, the more latitude docs will have in the way they prescribe it.

Here's some more ways Opdivo has been approved and is helping others:
  • Advanced renal cell carcinoma (11/23/2015)
  • Advanced non-squamous non-small cell lung cancer - after platinum based chemo (10/9/2015)
  • In the Nivo/Opdivo with Ipililmumab/Yervoy combo for BRAF V600 advanced melanoma (10/1/2015)
  • Advanced non-small cell lung cancer - after platinum based chemo (3/4/2015)
  • For melanoma, after failing ipi, and if BRAF positive, BRAFi (12/22/14) 
Additionally, Nivo/Opdivo has shown high response rates (87%) for relapsed or refractory Hodgkin Lymphoma.  Studies are currently looking at Opdvo combined with the anti-CD27 antibody, Varlilumab as well as Opivo/Yervoy combined with GM CSF (sargramostim) for melanoma.

NOW!  Let's see Opdivo approved for BRAF positive folks....FIRST line!!!  We've got ipi, a more toxic, less effective drug in melanoma...though a huge boon for folks who need it...approved for NED melanoma folks.  Let's get Nivo/Opdivo approved for the NED melanoma patients.  My ratties have proven its worth!!  Tunnel vision with FDA approvals is silly, non-nonsensical, and patients with deadly illnesses die while bureaucrats fail to put 2 and 2 together!!

Hang in there, ratties!  Slowly but surely, you are changing the world! love, c

Tuesday, November 24, 2015

Fall hike in Cades Cove

I was able to whisk B away for his special day.  We had a lovely, restful time in Townsend, riding through and hiking in Cades Cove.  While warmer and a bit wetter than the weather had been recently, it was still fun.  The leaves had already peaked, but there was beauty to be had nonetheless.

 Thanks for the time, Bentie - and the bear!  Until spring....   les

Saturday, November 21, 2015

PCR testing for melanoma

Polymerase chain reaction (PCR) is a technique that is used to amplify trace amounts of DNA (and in some instances, RNA) located in or on almost any liquid or surface where DNA strands may be deposited.  It is an exceedingly sensitive technique to detect molecules.  In everyday medicine it can be used to check for the presence of a wide variety of substances - pertussis from a nasal swab, chlamydia and gc in urine, viral load of HIV patients from their blood sample, fungus in skin scrapings, and even genetic mutations.  It would be super cool if we could utilize this technique to accurately identify the presence and characteristics of melanoma cells....both for diagnosis as well as monitoring effects of treatment.  Here are some peeps who are working on it:

SNPase-ARMS qPCR:  Ultrasensitive Mutation-Based Detection of Cell-Free Tumor DNA in Melanoma Patients.  PLoS One. 2015 Nov 12.  Stadler, Eder, Pratscher, et al.

"Cell-free circulating tumor DNA in the plasma of cancer patients has become a common point of interest as indicator of therapy options and treatment response in clinical cancer research. Especially patient- and tumor-specific single nucleotide variants that accurately distinguish tumor DNA from wild type DNA are promising targets. The reliable detection and quantification of these single-base DNA variants is technically challenging. Currently, a variety of techniques is applied, with no apparent "gold standard". Here we present a novel qPCR protocol that meets the conditions of extreme sensitivity and specificity that are required for detection and quantification of tumor DNA. By consecutive application of two polymerases, one of them designed for extreme base-specificity, the method reaches unprecedented sensitivity and specificity. Three qPCR assays were tested with spike-in experiments, specific for point mutations BRAF V600E, PTEN T167A and NRAS Q61L of melanoma cell lines. It was possible to detect down to one copy of tumor DNA per reaction , at a background of up to 200 000 wild type DNAs. To prove its clinical applicability, the method was successfully tested on a small cohort of BRAF V600E positive melanoma patients."

Still needs to be tested on a greater scale...but sounds like progress. - c

Thursday, November 19, 2015

St. George - love - an artist's eye...

My cuties!!!

Bag ladies!  It was cold y'all!  And sunny!

Bag ladies with Mr. GQ!

No stopping a photog...even for a photog!!

Fisher menz.....

Beauty and the beach!


So much fun.  So lovely to have shared the time.  Great thanks to Irina's artistry.  (I don't get many pics of my resident photog!!!)  She's really awesome, y'all.  Check her out:
 Irina Popova - The artist - Art and Photography

Love, c