Saturday, May 19, 2018

Sew Chaotically! - A coral Basic InstincT

My #basicinstinctshirt by Sasha went together perfectly and works well with any bottom!!!  I decided Roo needed one too.  When I found this super luscious and silky jersey from Mood, I know it would be just the thing!  And it could not have gone better with her wardrobe re-boot....

You may remember the wardrobe review and repair post!
....which included the purple ruched top, along with the Purple Work-out Top and the coral Faux Wrap Dress!
So now...The Sasha Basic InstincT!!!
I can't tell you how nice this pattern is!!!  It is perfectly drafted and so easy to dress up or down!
Again, Roo was a sport, letting me snag a photo before we ran off to our work out!  I know she'll get lots of use out of this top at work and play!
Seriously, y'all!!  You gotta check out Sasha!  Here's a link to her blog:  Secondo Piano  She makes the coolest things and includes lots of inspo on how to hack her very own pattern - Basic InstincT ( a t-shirt pattern).  And crazy woman!  As if that's not enough, the pattern is FREE!!!!!
Thanks, Sasha!  Sew Chaotically!!! - les

Thursday, May 17, 2018

Whatever it takes!!!

Melanoma steals so much from so many.  It frightens all of us if we think upon it too long.  It petrifies those newly diagnosed ~ almost beyond bearing.  Still, it has allowed me to meet, and know, and love, REAL heroes whose outlook on life, while forever changed, is nothing short of amazing.  They light my path.  They bring me smiles.  They inspire my efforts.  They give me strength.  I want to be just like them when I grow up!!!  So, for ALL of you there is this ~

(With much credit and appreciation to - Imagine Dragons!!!  Listen to the link, words below.)

Whatever It Takes - Imagine Dragons

Falling too fast to prepare for this
Tripping in the world could be dangerous
Everybody circling is vulturous
Negative, nepotist
Everybody waiting for the fall of man
Everybody praying for the end of times
Everybody hoping they could be the one
I was born to run, I was born for this.

Whip, whip
Run me like a race horse
Pull me like a ripcord
Break me down and build me up
I wanna be the slip, slip
Word upon your lip, lip
Letter that you rip, rip
Break me down and build me up

Whatever it takes
'Cause I love the adrenaline in my veins
I do whatever it takes
'Cause I love how it feels when I break the chains
Whatever it takes
You take me to the top, I'm ready for
Whatever it takes
'Cause I love the adrenaline in my veins
I do what it takes.

Always had a fear of being typical
Looking at my body feeling miserable
Always hanging onto the visual
I wanna be invisible

Looking at my years like a martyrdom
Everybody needs to be a part of 'em
Never be enough, I'm the prodigal son
I was born to run, I was born for this.

Hypocritical, egotistical
Don't wanna be the parenthetical, hypothetical
Working hard on something that I'm proud of, out of the box
An epoxy to the world and the vision we've lost
I'm an apostrophe
I'm just a symbol to remind you that there's more to see
I'm just a product of the system; a catastrophe
And yet a masterpiece, and yet I'm half-diseased
And when I am deceased
At least I'll go down to the grave and die happily
And leave the body and the soul to be a part of thee ~

I do what it takes.

Whatever it takes
'Cause I love the adrenaline in my veins
I do whatever it takes
'Cause I love how it feels when I break the chains
Whatever it takes
You take me to the top, I'm ready for
Whatever it takes
'Cause I love the adrenaline in my veins
I do what it takes.

And so we melanoma peeps do ~ whatever it takes.  At times, merely whatever it takes to make it through an hour, or day.  But, bit by bit, we grow stronger than melanoma.  No matter what that bitch tries to dish out.  Despite forever half diseased, we are a masterpiece!   

With sincere appreciation and remembrance - Artie, Patti, Josh, Juan, Ms. Ituah (and daughter), Bob, Santos, Dfeng, Jamie, Paul, and Rob's Adriana - you are forever part of my heart.

Great thanks to my dear J and F, Jeanne, Eric, and Ed.  You guys rock and are part of the foundation on which I stand. Tammy B, Danita, Ashia, Anita - you stand by me, watch me like mother hens, and put up with NONE of my BS!  It is a blessing.  Roo, your spirit and determination are contagious.  I would not be running or doing those push-ups were it not for you!!  Ruthie, your support and example are more than inspiring.  And B.... you're always there, for whatever it takes! 

And to all of those who think you can't...  Yes, you can!!!  Whatever it takes.

~ love and gratitude, les

Wednesday, May 16, 2018

In melanoma, if you are worried about your PD-L1 level....DON'T wig out yet!!!!

While a wide variety of folks have been gettin' folks fired up about the presence or absence of PD-L1 expression in relation to response to immunotherapy (checkpoint inhibitors)...there's this:

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.  Morrison, Pabla, Conroy, et al.  J Immunother Cancer. 2018 May 9.  
Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.  
Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.
PD-L1 positivity greater than or equal to 1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

Immunotherapy works in about 40% of melanoma patients, if you are talking about anti-PD-1 (Nivo/Opdivo or Pembro/Keytruda) and we REALLY need to figure out how to make that response rate better.  Here, researchers from 8 facilities looked at a lot of factors ~ PD-L1 expression, CD8 T cell infiltration, tumor mutational burden and other funky immune factors.  After examination of 231 patients (as best as I can tell), while PD-L1 positivity "correlated with response and OS...but demonstrated limited predictive performance."  "Comprehensive immune profiling demonstrated higher sensitivity (72%) compared to PD-L1 (34%) and tumor mutational burden (32%)."

Clearly, the presence of PD-L1 on your tumor is not the end all be all in determining response to immunotherapy.  Would that it were that simple!  But, y'all know melanoma don't play that way!!  Hang in there ratties!  - c

Friday, May 11, 2018

Sew Chaotically! - Another faux wrap dress, but coral and for Roo!!! M6884

Sew!!!  I plowed through my purple period with this little ruched knit top, M6282 and a cute mesh exercise top, M7610 for Roo!  Now for a coral cornucopia!!

First up is the faux wrap dress, middle left.  I made this one for myself a while back: 

Faux wrap dress - M6884

The pattern is super straight forward and though I had lowered the placement of the "tie" on mine, as it is placed rather high for most reviewers and I am tall, once I had Rose try on mine, I moved it back up almost to where the pattern places it for her.

And since neither of us are all about those bows, after a few wears, I removed them from mine, cutting off some length from the ties and adding snaps to attach them at the side.  Should I make this dress for myself again, I will probably leave the ties off entirely, but Rosie liked them on hers and followed suit with a hidden closure on the left side.

I think it looks so pretty on her!  She was even a good sport and let me snap a quick pic just after she rushed in from work as we were zooming out to our weekly Barre Cardio class!!!  The material is a very soft, lush, almost sweater knit and a little thicker than is comfortable for the season currently.  It will serve her well when school restarts in the fall!!  Part 2 of my coral cornucopia coming soon!  Sew chaotically! - les

Thursday, May 10, 2018

X4P-001, an oral CXCR4 inhibitor for melanoma, Phase 1 study examines results when given alone vs with pembro

Early days for this one...but, there's this:

X4P-001, an orally bioavailable CXCR4 antagonist, enhances immune cell infiltration and activation in the tumor microenvironment of melanoma.  Andtbacka, Pierce, Campbell, Yushak, et al. AARC April 2018.

The CXCR4/CXCL12 pathway plays a central role in the trafficking of key immune cells in the tumor microenvironment (TME). X4P-001 is an oral, selective, allosteric CXCR4 inhibitor. We hypothesize that the disruption of CXCR4/CXCL12 signaling by X4P-001 will favor an improved response to checkpoint inhibitors by modulating the immune cell profile within the TME and increasing CD8+ T cell infiltration. A biomarker-driven phase 1b clinical study is being conducted in melanoma patients to test this hypothesis (NCT02823405).

The primary objectives for the study are to evaluate the safety and tolerability of X4P-001 as a single agent and in combination with pembrolizumab in patients (pts) with metastatic melanoma, and to characterize the effects of X4P-001 alone and in combination with pembrolizumab on tumor immune cell infiltrates. Serial biopsies of cutaneous or subcutaneous melanoma lesions, peripheral blood mononuclear cells (PBMCs), and serum samples were collected pre-dose, after 3 weeks of X4P-001 treatment, and after 6 weeks of combination treatment. Biopsies were assessed by immunohistochemistry (IHC) and multiplexed immunofluorescence (mIF) for multiple markers, including CD3, CD8, FoxP3, PD-L1 and Granzyme B, and by NanoString® analysis for changes in gene expression. PBMCs were analyzed by flow cytometry for both lymphoid and myeloid cells. In addition, multiple serum markers will be assessed using the multi-analyte profile (MAP) platform.

As of September 15, 2017, 13 pts have been enrolled, and 11 have completed the study. The median age was 73 years (range 53-90). Of the evaluable pairs of biopsies, X4P-001 treatment alone increased CD8+ T cells, increased granzyme B signal, increased antigen-presenting machinery such as HLA-DR, and increased IFN-gamma gene expression signature scores in the TME. These biomarker responses were further enhanced when X4P-001 was combined with pembrolizumab. X4P-001 was well tolerated. AEs assessed as related to either X4P-001 or pembrolizumab at any time were diarrhea, maculopapular rash, fatigue, chills, and acute kidney injury. These data, along with additional biomarker measurements, will be presented.

Evidence of enhanced immune cell infiltration and activation is observed in the TME with X4P-001 treatment alone. Increased IFN-gamma gene expression signature scores after single-agent X4P 001 treatment support the use of X4P-001 to increase the likelihood of a response when combined with anti-PD-1 therapy. X4P-001 as a single agent and in combination with pembrolizumab is generally safe and well tolerated. Further in-depth biomarker analysis is ongoing as enrollment nears completion. 

So, real live ratties with metastatic melanoma (though there are only 13 of them, as of this report and only 11 had completed the study) were given X4P-001 alone or with pembro.  Samples of their tumor along with blood tests looking at the immune response were done before the drug, as well as at 3 and 6 weeks into treatment.  Researchers report that they saw increased activation and efforts by the immune system in the tumor microenvironment.  Because of this, they are hopeful that by giving X4P-001 with pembro, the likelihood of a response will be increased.

So...yes.  Early days and few patients examined on this one so far...but, here's hoping!  - c

Tuesday, May 8, 2018

When there is beauty....


And when your love and best friend knows just what you need...even better.  Thanks B.  Love and hugs to each of you. - les

Sunday, May 6, 2018

Vemurafenib and HSP90 for BRAF positive peeps with unresectable melanoma

Folks have been looking at many meds to add to targeted therapy so that melanoma peeps (who happen to be BRAF positive....about 1/2 of us) will not develop resistance to the positive effects of those drugs.  They have been looking at HSP90 (heat shock protein 90) as well as ricolinostat (an HDAC6 inhibitor) for some time now.  Here are some prior reports:  Heat Shock Protein 

Now, there's this: 

Combined BRAF and HSP90 inhibition in patients with unresectable BRAF V600E mutant melanoma. Eroglu, Chen, Gibney, Weber, et al. Clin Cancer Res. 2018 Apr 19. 

BRAF inhibitors are clinically active in patients with advanced BRAFV600-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888.

Vemurafenib (960 mg PO BID) combined with escalating doses of XL888 (30, 45, 90 or 135 mg PO twice weekly) was investigated in 21 patients with advanced BRAFV600-mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity.
Objective responses were observed in 15/20 evaluable patients (75%), with 3 complete and 12 partial responses. Median progression-free and overall survival were 9.2 months (95%) and 34.6 months, respectively. The most common grade 3/4 toxicities were skin toxicities such as rash (n=4, 19%) and cutaneous squamous cell carcinomas (n=3, 14%), along with diarrhea (n=3, 14%). Pharmacodynamic analysis of patients' PBMCs showed increased day 8 HSP70 expression compared to baseline in the three cohorts with XL888 doses greater than/= to45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP-client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy.

XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAFV600-mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAFV600-mutant melanoma.

Thanks, ratties.  We'll have to see if this moves any further along and/or if they will finally combine it with a BRAF/MEK combo which we already know does better than BRAFi alone! - c