Thursday, November 30, 2017

Safety nets and strong women.....

Yes, many men have more than helped me along my path in life and melanoma.  Dear B, Fred-o, Dr. Michaels, Dr. Weber...are just a start to the list.  Yet, there is an incredible system, an old and knowing sisterhood, that so many women, (And NO!!!  Not all women possess this wisdom...but still.....) from dear Ruthie and Rosie, to so many others near and far, neighbors and coworkers, that literally took me into their hearts and arms, giving me strength when I could not make it on my own.

Over ten years ago, I wrote this:  Women

 More recently, I recalled this post from 2011...
PPP = Pinky Pink Power Women...or... I sewed and created a new post and story ~

Sew Chaotically! - Pinky Pink M6752 and "pattern" from J Crew RTW tank!!!
Then there's the many times a wide variety of potty pics have figured largely in my world:

TB - From 2015: Happy Halloween...and then some!!!
For a better explanation read:  What to say and do....and NOT!!...for a cancer FRIEND (not patient)!

Then today...this, posted by Jeanne...brought memories flooding back and sweet tears to my eyes:

Yes, I have been carried in that net and heard those songs.  Great thanks, big hugs, much love, with laughter that makes your tummy hurt and tears flow ~ to each of you.  love, c

Wednesday, November 29, 2017

ERK inhibitor - (BVD-523) Ulixertnib. A new approach to targeted therapy for melanoma? Here's hoping!!!

Remember this crazy diagram????

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (ulixertinib). Germann, Furey, Markland, et al. Mol Cancer Ther. 2017 Sep 22.

Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF- and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic anti-proliferative effects in a BRAFV600E mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK targeted therapy. Based on these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway  (NCT01781429NCT02296242 and NCT02608229).  

I like ERK!!!  I mean, I like it as I've always liked onomatopoeia!!!  (Don't you just love to say THAT word???  Onomatopoeia!!!)  I like "ERK!!!" like I like "BAM!!" in comics.  Or "tic tock" in Mother Goose and scary stories!  When I was a kid, my sisters and I played dramatic pretend games, with one of us telling the other, "Pretend like....." .  Then, the other...would indeed pretend like - whatever  - as had been prescribed for the story line.  Words like "POW!!!" and "ERK!!!" figured largely in abrupt crashes and conclusions.  So....yeah.  I like ERK!!!  Let's put the brakes on melanoma!  ERK!!!! (Thanks to the mice.  Here we go, ratties!) - love, c

Sunday, November 26, 2017

HDAC inhibitors for melanoma....what are they again????

One of my first posts about HDAC inhibitors was back in 2016:  HDAC (Histone deacetylase) inhibitors for melanoma

Noting that researchers had hopes that in melanoma they could be used to try to overcome resistance to BRAF inhibitors, though at that time...not too much had come of them.

At ASCO this year, there was this:  ASCO 2017: Pembro plus Entinostat (histone deacetylase inhibitor - HDAC)

Where as the abstract discussed combining Pembro (now Keytruda) with entinostat, I noted:  "Existing evidence supports the hypothesis that HDAC inhibitors (HDACi) may sensitize melanoma cells to immunotherapy and targeted therapy and hence bear therapeutic potential concurrent with immune checkpoint blockade or BRAF and MEK inhibition."

Now, there's this:

HDAC inhibitors enhance the immunotherapy response of melanoma cells. Booth Robers, Polkepovic, et al.  Oncotarget. 2017 May 17. eCollection 2017 Oct 10.  
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney. Knock down of HDAC1, HDAC3, HDAC8 and HDAC10, but not HDAC6, recapitulated the effects of the HDAC inhibitors on the immunotherapy biomarkers. Using B16 mouse melanoma cells we discovered that pre-treatment with AR42 or sodium valproate enhanced the anti-tumor efficacy of an anti-PD-1 antibody and of an anti-CTLA4 antibody. In the B16 model, both AR42 and sodium valproate enhanced the anti-tumor efficacy of the multi-kinase inhibitor pazopanib. In plasma from animals exposed to [HDAC inhibitor + anti-PD-1], but not [HDAC inhibitor + anti-CTLA4], the levels of CCL2, CCL5, CXCL9 and CXCL2 were increased. The cytokine data from HDAC inhibitor plus anti-PD-1 exposed tumors correlated with increased activated T cell, M1 macrophage, neutrophil and NK cell infiltration. Collectively, our data support the use of pan-HDAC inhibitors in combination with kinase inhibitors or with checkpoint inhibitor antibodies as novel melanoma therapeutic strategies.
Here's hoping...again. - c

Saturday, November 25, 2017

Sew Chaotically! - Kimono Sashiko Jacket - Lisette B6464 (A little late in posting...but better late than never!!!)

I planned to make a kimono jacket with Sashiko embroidery when I started on this top:

Annie Top by Tessuti
But which kimono jacket pattern to use!!!  I have enjoyed making several Lisette patterns:
This Blanket Coat

This dress....
and this jacket from her Passport pattern

And most recently, I used the pattern below for this little top in my Summer of Basics make-along! 
I figured this jacket included would be perfect!

After creating my stencil, I carefully traced it onto the cuff and neck band pieces.  Then, I decided exactly how I wanted to stitch the "flower" part of the design.  Consistency is important in having your Sashiko embroidery look its best.

I did all the long straight rows and came back around, stitching all the circles.
I made a straight 12.  The pattern comes together very easily.  I flat felled the side seams so the insides would have a clean finish. My only change was in construction. I sewed the cuff to the sleeve flat and then attached the sleeve flat, which allowed me to stitch the sleeve and sides in one go.  You turn up the cuff to the inside, so your seam is hidden. 
I am quite pleased with how it turned out.  The fabric is a linen blend, which is sort of the best of both you get a linen look with much easier care and without the wrinkles!  The only difficulty is that though the fabric seems like a simple navy on its's a little tricky when you pair it with other blues!  I made it as summer was waning, so it has seen limited use this fall with the cooler temps.  I can't wait to put it in serious wardrobe rotation in the spring!

Then, it struck me that this jacket would be cozy in fleece!
So I made one for my dear sweet Danita!

She's been with me...
through highs and lows!!

And because I had extra fabric...  What the heck?  Another for me!
Sew Chaotically! - les

Thursday, November 23, 2017

ISF35 - the viral vector for a CD40 agonist - used as an intratumoral/intralesional melanoma treatment!!!

On the subject of intratumoral treatment of melanoma - drugs that are injected directly into the tumor, as the prior post on IMO-2125, a TLR agonist discussed, along with ALL these other intralesional/intratumoral therapies covered here:  ASCO 2017: All things intralesional/intratumoral
 - we've learned a couple of things:

1.  These drugs can have significant "by-stander" effect.  Meaning - they can kill not only the tumor they are injected it...but others...distant from the site of the injected tumor.

2.  As many melanoma experts said years ago, they will most likely turn out to be most effective when paired with systemic immunotherapy (as most of the research that is on-going is doing currently.

But...there's another one on the horizon.  It's been a long time in coming.  I posted this back in 2014:

CD40 Antibody therapy for melanoma....another way to activate the immune system?

And now, there's this:

Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain. Singh, Vianden, Cantwell, et al. Nat Commun. 2017 Nov 13.

CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8+ T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8+ T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy. Triple combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and noninjected subcutaneous tumors, as well as melanoma tumors in the brain. Therapeutic efficacy is associated with increases in the systemic level of tumor-specific CD8+ T cells, and an increased ratio of intratumoral CD8+ T cells to CD4+ Tregs. These results provide a proof of concept of systemic antitumor activity after intratumoral CD40 triggering with ISF35 in combination with checkpoint blockade for multifocal cancer, including the brain.
A triple-decker approach!!!  I like it!!  Now where is the slick MD Anderson poster boards for this one?????

Fingers crossed, ratties!  Fingers crossed. - c

Wednesday, November 22, 2017

Sew Chaotically!! - African Wax Print top for a beautiful friend!!!

I had so much fun with my first foray into the use of African Wax Prints!!!

Here's the whole story:  Sew Chaotically! - African Wax Print Butterfly dress!!!
My dear friend, Ashia, has always been hugely and sweetly supportive of my sewing efforts!  But you should have seen her face light up in admiration of this fabric in particular!!  Despite my wild abandon in cutting out the pieces of my dress with zero focus on conservation of fabric....thinking only of which swath of color I wanted to place where...and the fullness of the dress itself..... I STILL had loads of fabric left.  6 yards is a lot, y'all!!!  So, I took it into my head to make a top for her.  I had her loan me a simple sleeveless, tunic top that she liked and fit her well.  I started with a basic paper tracing of front and back, with a line for the bust dart.  I don't know what I was thinking...something along the lines of:  just cut that line and slip in extra space....but quickly discovered what those with a brain more spatially related than mine would have intuitively grasped!  That WON'T work!!! was onto the internet to learn how to do a full bust adjustment!!!  (If you have looked at this blog for half a minute, you KNOW that is something for which I have had no prior need!!!!)  If you ARE in need, these two links were really helpful:

Workroom Social: Full bust adjustment tutorial

Craftsy: Full bust adjustment

It seems pretty clear and straightforward...NOW....but it pinched my brain for a minute there!!!

And there she is!!!  The top and my beautiful friend!!!  Love you, Ashia!!! - les

Monday, November 20, 2017

IMO-2125, a TLR agonist combined with Yervoy (ipi) for folks with melanoma refractory to anti-PD-1

So, one of the MRF peeps put up a bit of an ad for this treatment...not entirely sure why, as that is not usually their role.  Perhaps they were just letting folks looking for a treatment option after failing anti-PD-1 know this trial was enrolling.  But, with so little intel out about this study and so many other options available - it piqued my interest.  It was quickly apparent that it is hard to find much info on it other than the super slick "presentations" made by the company who makes it, Idera, and the company who wants you to join their trial, MD Anderson, like these:

A Phase 1/2 trial of intratumoral (i.t.) IMO-2125 (IMO) in combination with checkpoint inhibitors (CPI) in PD-(L)1-refractory melanoma - out of MD Anderson

Idera Press Release for investors

But, when my intrepid medical researcher, partner in crime and all things got on the case, he found this:  Melanoma News Today - report from April 2017

It reads as follows:

Combining IMO-2125 and Yervoy Shows Promise in Certain Metastatic Melanoma Patients   By:  Daniela Semedo, Melanoma News Today, April 2017.

Combining {Idera's] intratumoral IMO-2125 treatment with Yervoy (ipilimumab) may be a promising treatment approach for patients with metastatic melanoma who are refractory to anti-PD-1 therapies, according to preliminary data from a Phase 1/2 clinical trial.
We are very pleased with the progress to date in the Phase 1 dose escalation trial of IMO-2125 in combination with ipilimumab, and with the outcomes observed,” Joanna Horobin, Idera’s chief medical officer, said in a press release. (Possibly the one I noted above.)

IMO-2125 in combination with ipilimumab demonstrated preliminary evidence of meaningful clinical activity in this anti-PD-1 refractory metastatic melanoma patient population which represents a high unmet medical need,” she said.
All dose levels have been well tolerated and did not exacerbate the safety issues commonly observed with ipilimumab,” Horobin said. “Furthermore, data from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”
IMO-2125, a toll-like receptor (TLR) agonist, is designed to activate cells from the innate immune system and induce the production of interferon — a potent activator of the immune system. Together, this is thought to lead to the infiltration of tumor-killing T-cells.
Because tumors have developed a method to impair T-cells from recognizing and attacking them, Idera believes that the drug could work in synergy with known and approved immune checkpoint inhibitors.
The open-label Phase 1/2 study (NCT02644967) was designed to assess the safety and preliminary effectiveness of intratumoral IMO-2125 in combination with the CTLA-4 inhibitor Yervoy or the PD-1 inhibitor Keytruda (pembrolizumab) in patients with metastatic melanoma who progressed after receiving anti-PD-1 therapies.  The study was set to be conducted in two parts: a dose-escalation portion (Phase 1) to evaluate safety and tolerability of multiple dose levels, and a Phase 2 expansion portion to assess efficacy.
While the Phase 1 dose escalation of IMO-2125 in combination with Keytruda is ongoing, the company has now announced that the Phase 1 part assessing IMO-2125 plus Yervoy has met the pre-specified futility assessment, meaning that the combination reached the established efficacy cut-off.
The company announced that all dose levels of IMO-2125 were well tolerated, and that the 8 mg dose level was established as the recommended Phase 2 dose.
Nine participants out of an expected 21 have enrolled in the Phase 2 portion of the trial assessing the objective response rate of IMO-2125 in combination with Yervoy. Data will be compared with historical controls treated with Yervoy alone.
Houston’s MD Anderson Cancer Center will continue to lead the study and will be joined by other clinical sites. Idera expects to have overall response rate (ORR) data early next year.
I am very encouraged by the tremendous progress that has been made to date to advance us to this important stage in IMO-2125’s development cycle,” said Vincent Milano, Idera’s CEO. “There is a very clear unmet medical need for those patients for whom current checkpoint inhibitor therapies are not providing adequate solutions.
We are incredibly focused on advancing this program as rapidly as possible for these patients, and we are also looking forward to exploring areas outside of melanoma in which intratumoral IMO-2125 may also serve an important role through its unique mechanism of action within the tumor microenvironment,” he said.
Idera also said it has started meeting with regulatory agencies about the best path to follow to register the combined treatment of IMO-2125 and Yervoy in patients with PD-1 refractory metastatic melanoma.
In addition, the company said the Phase 1 clinical trial evaluating the combined treatment of intratumoral IMO-2125 and Keytruda in PD-1 patients with refractory melanoma is enrolling as planned.  Moreover, a Phase 1 clinical trial evaluating intratumoral IMO-2125 alone (NCT03052205) in multiple tumor types should be enrolling the first patient in coming months.
Hmmm.....  Well, it is certainly a fact that we have folks who fail to gain effective control of their melanoma with anti-PD-1 and it's 40% response rate, leaving them in desperate need of an effective therapy!  It is also true that I encourage and fully support looking at any and all possible treatments to help them.  Yet, I remain a little puzzled here.  This statement sounds strong, but is substantially lacking in, hmmm....what's the word??????  " from multiple parameters of immune markers from tumor biopsies have been very informative in establishing proof-of-mechanism and supporting the dose selection for the Phase 2 portion of the trial.”  Oh!  I know what it is....DATA!!!!!!!!!!!!!!!  This report tells us NOTHING about how the folks in the phase 1 trial are doing!!!

An interesting aside:  The name TLR, toll-like receptor, came from the appearance the fruit fly larvae developed when used as subjects by researchers to isolate the molecule's function.  The larvae in whom the receptor was changed, looked very peculiar, or "droll", according to the German researchers who won a Nobel prize in medicine for this work.  And the German word for "droll" (i.e. funny) is "toll"!  The more you know....

While I hope IMO-2125 will absolutely be the cure for ever so many cancers, including melanoma, we need to remember that current intratumoral/intralesional therapies that are being combined with immunotherapy daily, to good effect, are available for melanoma patients in need and come WITH data supporting their efficacy!  Here's a post reviewing a wide variety of them and the DATA required for them to sally forth:

ASCO 2017: All things intralesional/intratumoral

If TLR agonists become the next great thing....will we all be cured of our melanoma AND have a great sense of humor...or just look a little funny?????  Hang tough ratties!  The road is long with lots of tolls!  And I mean LOTS!!! - c

Sunday, November 19, 2017

Back to the cooties in our guts....again!!!

We all want a magical cure for our melanoma!!  Short of that, we certainly want to do whatever we can to make sure the treatments we do utilize work to their very best effect!  In that vein, various studies have looked at the bacteria in our intestines, our 'microbiome' (or...the cooties in our gut!!), and how they may interact with immunotherapy.  Here is a prior post with links to several studies:

ASCO 2017: Melanoma, anti-PD1 and the microbes in your gut

Now there's this: 

Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Gopalakrishnan, Spencer, Nezi, et al.  Science. 2017 Nov 2. 

Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity and relative abundance of Ruminococcaceae bacteria in responding patients. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

Best I can tell you is what I've said before ~ it is likely that our best bet is to avoid antibiotics unless really needed, eat kimchi, sauerkraut, yogurt and kefir!  Or.....fecal transplant, anyone???! 

Yum!!! - c

Thursday, November 16, 2017

Sew Chaotically! - Pinky Pink M6752 and "pattern" from J Crew RTW tank!!!

When Rosie was a little girl, she had an older brother whom she adored and Power Rangers were a thing!!!  However, she refused to accept the mantle of 'Pink Power Ranger' and held the Pink Barbie Power Ranger-esq character in great contempt!  So....Pinky Pink Power Woman was born!!!

A Pinky Pink Power Woman who was very proud of her eye the way!!!
Can you appreciate her fierce pinkness????
When I was in treatment with immunotherapy (nivolumab, now Opdivo) and incredibly painful (and utterly worthless) peptide vaccines...she made t-shirts for the Pink Peptide Posse!!!  [On the back of Ruthie's reads "TROUBLE" while the back of mine reads "DOUBLE!!!"  Does she know us or what???  And, yes, we did wear them together for some sessions!!!]  

Anyhow, though some think pink is a bit 'twee' for fashion, I love it. When I found this gossamer-like pink knit (fifth from the bottom above) in a shop in Walthamstow Market, London, I had to have it!!!  But, what in the world to do with such transparent, pink, delicate stuff????
Well, this.....
I had already used this pattern to make a cowl neck dress:  Here!  And got it into my head that I would make it into a top!!  But a top from fabric that flimpy [Yep! Flimpy is a thing!!!] and see-through...I would need an undershirt!  No worries, I could make that, too!
I've had this bias cut racer back tee from J Crew for years!
It fits me perfectly and I love it!!!  Plus, I liked the idea of the straps being slightly visible with the cowl neck top.  I should be able to use it as a pattern, right????
So....I did!!!  The shoulder straps came out a little thinner than I prefer, because the bias binding I made from the fabric was a little more cantankerous than anticipated!  I'll keep that in mind for my next one.
I really love it!
Now for the top!  Ta-dah!!!
I am Scott Boy Stoked about how this came together!!!

I had so much fun turning this simple idea into TWO garments I really like.  With trousers it is work ready.  With my city joggers, I feel ready for travel - to Italy - or the grocery.  With a pencil skirt it is dinner party perfect!  A Pinky Pink Power Woman outfit indeed!!!  (I hope the sweet, funny lady I met in Walthamstow while waiting to get our respective pieces cut [mine, this pink...hers a black terry] has made her "walking club" jacket!!!)  Wherever you are, whatever you're making ~ Sew, and LIVE, Pinky Pink Chaotically! - love, les
P.S. Thanks for being my Pinky Pink Power Woman Inspo, Roo!!!  I love you!!! - mommy

Wednesday, November 15, 2017

Circulating DNA - predicting survival in patients with resected Stage II/III melanoma

Wouldn't if be wonderful if a simple blood test could tell us if we have melanoma, what type of melanoma, and quantify the "amount" of melanoma...thereby giving us specific reports about whether our disease status is progressing, resolving, or stable?  Just think, with a test like that, we could quickly determine if we are responding to a particular therapy....or not!

I have posted data on this topic many times!  This link will take you to my last post and includes many more within:  ASCO 2017: Circulating DNA to measure response in melanoma

Now there's this:  

Circulating tumor DNA predicts survival in patients with resected high risk stage II/III melanoma. Lee, Gremel, Marshal, et al.  Ann Oncol. 2017 Nov 3.
Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma.
We performed droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial.

Mutant BRAF or NRAS ctDNA was detected (greater than/= to 1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval and distant metastasis-free interval versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status (PS) and disease stage. Five year overall survival (OS) rate for patients with detectable ctDNA was 33% versus 65% for those with undetectable ctDNA. OS was significantly worse for patients with detectable ctDNA and remained significant after adjustment for PS.

CtDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy.

Soon!!  I hope, soon...this test (or something like it) will be refined and readily available for melanoma patients of all stages!!! - c

Sunday, November 12, 2017

Sew Chaotically! - The Basic InstincT t-shirt by Sasha!!!!!!!!!!!!!!

I have learned a great deal from many sewists through their blogs, tutorials, and other posts on various social media.  Some I simply watch, trying desperately to absorb all their tips and techniques.  Luckily, others have become peeps!!!  Amazing people...who touch my heart, make me laugh and teach me about life...not just sewing.  For a start there's Oonaballoona - aka Marcy Harriell who, via her blog, provided many tips for fabric shopping in NY, inspo and advice for the use of African Wax Prints, creates beautiful, personally authentic garments, and makes me laugh out loud!  There's Tilly, of Tilly and the Buttons, who inspired much of my London fabric shopping.  There's Rochelle, of Lucky Lucille who endlessly inspires me with her art, beautiful garments, work ethic and personal strength in not only enduring, but triumphing over personal challenges. I adore all the women who make up Mix and Sew.  French style is for real, y'all!!  I would be thrilled to be part of such a sewing group!  I adore their exuberance, willingness to admit flaws, and lovely sisterhood!

But, today -  I would like to introduce you to Sasha!!!  Her blog is Secondo Piano (that would be 'Second Floor' in Italian). I love her style, her passion!  Her dedication to authentic, sustainable fabric, fashion, and the way we look at garments, interpret, and make choices as "makers" inspires me daily!  If that is not enough, she MAKES great patterns!!!  AND....they are free!!!  Just subscribe to her amazing site!!!

Sew.....I happily embarked on making her Basic InstincT t-shirt!  To quote Sasha:
"I chose the relaxed cut because I think it’s a more contemporary silhouette and I personally do not like so much having my bra line showing. The crew neckline I just adore for its boyish, nonchalant look in a woman’s garment. I think it looks great under a blazer or a cardigan and can easily be lowered. I wanted this pattern to be a sort of I wanted this pattern to be a sort of blank canvas you could potentially transform into your own beautiful painting."

Great thanks to my B for printing and putting together another pattern.  (If you want, you can print only the size you prefer!  But, when you've got a helper willing to continually print and put together patterns for you...he can do it any way he wants!!!)

Here we go!

I used a drapey cotton knit from Mood I picked up a bit ago...

...and yes, one should make a muslin...but, I can't - be bothered!!!  I made the "small" with no changes, and luckily...the fit is fabulous!!!

I did ALMOST mess up my AMAZING t-shirt by being stubborn!!!  I was set on having my stripes go opposite to the body of the shirt on the neck band, and there was less stretch in that direction....but....I made it work!!!  

The Basic InstincT t-shirt  easily dresses up or down.  It plays well with skirts or pants, alone or with a jacket.  (Here I've added my Morris Blazer!) I can see this pattern becoming the wardrobe staple Sasha envisioned!  I am looking forward to other t's and dresses using this pattern!

Thanks, Sasha. And not just for this t-shirt!  Thanks for being you!!!  Sew chaotically! - les

Friday, November 10, 2017

Melanoma patients continuing Nivo after having adverse reactions to the ipi/nivo combo??? Yes, you can!

Though management can be tricky, docs have been saying from some time that folks CAN tolerate anti-PD-1 if you have previously had adverse reactions to ipi or a pre-existing autoimmune process.

Here's a report from ASCO 2016: Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders (AD) or major toxicity with ipilimumab (IPI).

And another post that includes several sources from this year:  Patients with preexisting immune disease, melanoma, and treatment with Anti-PD-1? Yes, this can be done. Yes, autoimmune flares should be treated with immunosuppressive therapy while on immunotherapy. And YES!!!! These patients can still attain a response!

Now there's this:

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Pollack, Betof, Dearden, et al.  Ann Oncol. 2017 Oct 11.

Combined CTLA-4 and PD-1 blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known.
We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.

Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids, and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (6 grade 1-2, 7 grade 3-4, 1 grade 5 Stevens-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% vs. 28%). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2, 6 grade 3-4). Duration of steroid taper, severity of initial irAEs, and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% vs. 31%).

Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in select patients.

Clearly, not a walk in the park for some...but a return to nivo alone after a reaction to the ipi/nivo combo proved doable for about 60% of these patients with significant reactions requiring immunosuppression therapy for their side effects!  

Take care ratties!!  It's a tough world at NIMH!!!! - c

Thursday, November 9, 2017

Review of adjuvant treatment in Stage III melanoma and "death knell" for ipi and interferon in that role!!!!

Those who have read this blog for half a minute know that I have been yelling about the need for adjuvant treatment in melanoma that is NOT interferon....and after the response rates we know we can attain with anti-PD-1 products and BRAF/MEKi...NOT ipi either!!!  Here is a recent post with links to more within:

Adjuvant treatments in melanoma - They WORK!!! Now, let's make sure people can get them!!!!!

Now there's this:

Dabrafenib/Trametinib Combination and Nivolumab New Adjuvant Treatment Options for Stage III Melanoma. Prime Line, October 5, 2017.

The current adjuvant treatment options for high-risk patients with resectable melanoma include interferon and the cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab. Compared to placebo, ipilimumab (10 mg/kg) prolonged relapse free survival (RFS) and showed significant 5-year survival benefit in high-risk patients with melanoma, but at the cost of serious toxicity. In the metastatic setting, combinations of BRAF/MEK inhibitors in patients harboring BRAF mutations, and immunotherapy with programmed death receptor 1 (PD-1) inhibitors (± ipilimumab) regardless of BRAF status are standard of care based on evidence of survival benefit and manageable toxicity. The efficacy of these regimens has, thus, been investigated in the adjuvant setting, and results from two of these studies presented at the third Presidential Session at the 2017 European Society for Medical Oncology (ESMO) Congress are practice changing.

The COMBI-AD trial (N = 870), presented by Axel Hauschild, MD, PhD (University Hospital Schleswig-Holstein, Kiel, Germany), compared the combination of dabrafenib (150 mg twice daily) and trametinib (2 mg daily) to placebo in patients with resected, high-risk, stage IIIA-C melanoma with BRAF V600E/Kmutation. At 2.8 years follow-up, the combination of dabrafenib and trametinib had significantly improved RFS compared to placebo (not reached vs 16.6 months). The 3-year RFS rate was 58% with the combination compared to 39% with placebo. The benefit of dabrafenib plus trametinib adjuvant therapy was seen across all patient subgroups, regardless of disease stage or risk factors. Furthermore, combination therapy significantly improved overall survival (OS), with 3-year OS rates of 86% with combination versus 77% with placebo. Dabrafenib plus trametinib was associated with an increase in adverse events (AEs) compared to placebo (grade 3/4: 41% vs 14%), but there were no deaths due to AE. A greater number of patients receiving the combination discontinued treatment due to AE (26% vs 3%), with the most common reasons being pyrexia and chills. In his conclusion, Dr Hauschild highlighted the RFS and OS benefits of dabrafenib plus trametinib, along with the manageable safety profile, indicating that this combination should become a new treatment option for patients with resected, stage III, BRAF-mutated melanoma. Results from the COMBI-AD trial were simultaneously published in The New England Journal of Medicine.

Jeffery Weber, MD, PhD (New York University, New York, New York, United States), presented results from the phase III CheckMate-238 trial (N = 906), which compared one year of adjuvant therapy with nivolumab (3 mg/kg IV every 2 weeks) to ipilimumab (10 mg/kg IV every 3 weeks for 4 doses, then every 12 weeks) in patients with resected stage III/IV melanoma. Significantly more patients treated with nivolumab remained relapse-free at 18 months compared to ipilimumab (66% vs 53%). Relapse-free survival benefit favored nivolumab regardless of PD-L1 expression level, disease stage, or BRAF mutation status. Adjuvant treatment with nivolumab was more tolerable than ipilimumab. There were fewer grade 3/4 treatment-related AEs in the nivolumab arm (14% vs 46%), and fewer patients treated with nivolumab experienced a treatment-related AE leading to discontinuation (8% vs 42%). There were no treatment-related deaths in the nivolumab group, while 2 patients in the ipilimumab group died due to AE. Dr Weber concluded that nivolumab should be considered as a new standard treatment option for patients with resected stage IIIB/IIIC/IV melanoma, regardless of BRAF mutation status. Results from this trial were also simultaneously published in The New England Journal of Medicine.

In their discussions of these studies, Alexander Eggermont, MD, PhD (Gustave Roussy, Villejuif, France), and Reinhard Dummer, MD, PhD (Cancer Center Zurich, Zurich, Switzerland), indicated that these trials represent the death knell for both ipilimumab and interferon as adjuvant therapies for melanoma. Moving forward, either nivolumab or dabrafenib plus trametinib will be the adjuvant therapy of choice for stage III melanoma, with treatment choice dependent on BRAF mutation status and physician and patient preference.

Additional reiteration (if you're into redundant redundancy) was noted in an editorial by Lynn Schuchter M.D. in The New England Journal of Medicine, published today:

Adjuvant Melanoma Therapy - Head-Spinning Progress

There she states, in part:

"Every year in the United States, approximately 87,000 patients receive the diagnosis of melanoma. Although most of these patients are cured with simple excision, those with node-positive, stage III melanoma are at increased risk for distant metastasis and death. To date, the Food and Drug Administration (FDA) has approved three adjuvant therapies for such patients, all of which are immunotherapies: high-dose interferon alfa-2b, pegylated interferon alfa, and high-dose ipilimumab (10 mg per kilogram of body weight).  Concerns about the marginal efficacy of these drugs (especially the interferon-based agents) and considerable toxicity (all three drugs) have limited their use. Therefore, the current standard of care for patients with node-positive melanoma includes observation without therapy, the use of one of the approved adjuvant therapies, or participation in a clinical trial."

She goes on to note the approval of "8 new drugs for the treatment of melanoma, seven of which have improved survival" - noting specifically the use of BRAF/MEK inhibitors and immunotherapy over the past 5 years - continuing:   "With these new approaches, some patients have been cured and many have seen remarkable improvements in symptoms...and duration of life.  The median overall survival of patients with disseminated melanoma has increased from 9 months before 2011 to 2 years or more."

As does the report above, she notes the results of the Weber presentation of the CheckMate 238 trial and the COMBI-AD trial.  Stating further:   "How do these results compare with those currently approved adjuvant therapies in patients with node-positive melanoma?  High-dose interferon...was approved more than 20 years ago and has been extensively studied...and showed no benefit in overall survival.  [It] has been associated with substantial toxic effects...the majority of patients... [fail to complete] 1 year of therapy, and the frequency of Grade 3/4 events has been more than 65%. 

Adjuvant high-dose ipilimumab was approved by the FDA 2 years ago on the basis of the results of EORTC 18071, which compared ipi with placebo...[and] significant benefit of overall survival was reported [with ipi]...Although high dose ipi has been shown to be effective, the toxicity of ipi at a dose of 10 mg/kg continues to pose a major challenge as an adjuvant therapy.

...Adjuvant therapy with nivo in patients with node-positive melanoma may now be considered a new standard of care, regardless of BRAF status.  On the basis of efficacy and safety, nivolumab, unequivocally, is a better choice than interferon or high-dose ipilimumab.  Adjuvant combination therapy with dabrafenib and trametiib is also an option for patients with node-positive BRAF-mutated melanoma.  Testing of melanoma tumors for the presence of BRAF mutations may now become standard in patients with node-positive, stage III melanoma.  There is no longer a role for adjuvant interferon in patients with  node-positive melanoma."

So, there!!!

Come on, FDA peeps!!!  If you or your loved one were affected...these therapies...not the crap you approved years ago....are the ones YOU would want!!! - c

Wednesday, November 8, 2017

A look back - ipi and pembro

Here are couple of review papers looking at ipi and pembro ~

Real world treatment patterns and outcomes among metastatic cutaneous melanoma patients treated with ipilimumab. Mohr, Ascierto, Arance, et al.  J Eur Acad Dermatol Venereol. 2017 Oct 17. 

There is a scarcity of real-world data on treatment patterns and outcomes among advanced melanoma patients treated with immunotherapies including ipilimumab, an anti-CTLA-4 antibody approved since 2011.  To evaluate ipilimumab and post-ipilimumab treatment patterns and outcomes among patients with advanced melanoma in Australia, Germany, Italy and Spain following regulatory approval.  Retrospective multicentre, multinational, observational chart review study. Data were extracted from the start of ipilimumab therapy until the end of at least 40 weeks of follow-up, or death.
Data from 371 patients (Australia, 103; Germany, 152; Italy, 76; Spain, 40) were analysed. Mean age was 65 years; 62% were male. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 or 1 for 94%. In 67%, ipilimumab was initially received as second-line or later therapy. Patients received on average 3.4 ipilimumab doses. The ipilimumab-refractory cohort comprised of 226 patients. Of these, 17% in Australia, 47% in Germany, 29% in Italy and 14% in Spain received another anti-melanoma treatment after ipilimumab including chemotherapy in 26% and BRAF/other kinase inhibitors in 11%. Ipilimumab-refractory patients who received post-ipilimumab treatment showed a 40% reduced hazard of dying than those not receiving treatment after ipilimumab, after adjustment for potential confounders.

During the time observed, ipilimumab was mainly used as second-line or later therapy. A significant proportion of patients received post-ipilimumab therapy, most of which was chemotherapy. Nevertheless, overall survival following progression on ipilimumab treatment remained poor, highlighting the need for research to develop more effective end-of-life treatment options.

Sadly, yep.  We knew that.  There is also this:  

Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program. Gangadhar, Hwu, Postow, Hamid, Daud...O'Day, Hodi, Pavlick, et al.  J Immunother. 2017 Nov/Dec.

KEYNOTE-030 ( ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% in the treated population (n=947) and 22.1% in patients who had greater than/= to1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced greater than/= to 1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced greater than/= to 1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

Remembering that this was back in the day, when in order to attain pembro, you had to have "progressed after standard-of-care therapy" (meaning ipi and BRAFi - if BRAF positive) - a circumstance which we now know provides a LESSER response to immunotherapy like pembo and nivo - Yep.  We knew this, too!!

While a look back is essential for progress and incredible strides have been made in treatments available for melanoma patients in the past 5 years,  a best case 40-50% response rate leaves far too many in need of effective therapy.  Come on researchers!!!  Ratties are counting on you.  Let's move forward....FAST! - c