KEYNOTE-001: Melanoma patients treated with Pembrolizumab (Keytruda) - 5 year survival outcomes

The KEYNOTE-001 study which administered Pembrolizumab (Keytruda) to melanoma patients with advanced disease and started back in 2011 has provided a great deal of data over the years.  Here are some of those reports:  KEYNOTE-001 reports over the years

Now there's this:

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.   Hamid, Robert, Daud, Hodi,…, Wolchok,…, Weber,…, Ribas.  Ann Oncol. 2019 Jan 31.

Pembrolizumab demonstrated robust antitumor activity and safety in the phase 1b KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.

Patients aged greater than/= to 18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cutoff, September 1, 2017).

KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months and 38.6 months, respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months and 16.9 months, respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cutoff; the longest response was ongoing at 66 months. Four patients (all with prior response of complete response) whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cutoff). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.  This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.

Good news, especially back in 2011.  Good news regarding durability of response.  Good news regarding re-induction with a second course for those in need.  Still in need of treatments that garner a complete response in MORE melanoma peeps.  Thanks, ratties. - c

March FORTH ~ no matter the tempest that surrounds you...

We are here.  Together.  On my favorite day.  Lucky to be able to live and love and continue to March FORTH!!!  (Here's a retrospective/explanation with links and beauty within!)

Despite the ugly all too easily found in the world - across the globe and across the hall - we will MARCH FORTH!!!  Despite the hurt and injustices that dear ones experience all to often - we will MARCH FORTH!!!!  Despite the struggles with ill health, poor treatment, and lack of access that far too many experience - we will MARCH FORTH!!!  TODAY on this most hopeful of days, and all the others in between - WE WILL MARCH FORTH!!!!!!!!!!!!!!!

Marching through life is not easy.  Life doesn't roll that way.  But, no matter the tempest in your teapot, you are loved.  You are worthy.  You can - MARCH FORTH!!!  Knowing all the while, you will never March Forth alone.  ~ love, les

Chaotic Cookery! ~ Thanks to Chrissy Teigen's: Cravings and Hungry for More

How do you thank someone for being there for you no matter what?  What do you say to let them know how much you appreciate their sleepless nights on uncomfortable cots and incommodious chairs in nasty hospital rooms?  For wiping your stanky ass...over and over...because you can't?  For coming when you call ~ no questions asked?  Who research, plan, prep, travel with, and prepare amazing meals for your recovery?  For giving up EVERYTHING they are busy with in their lives - family, fun, activities, work - for you?  You can't.  There are no words.  There are no things.  Nothing can express what I feel.  Nothing will ever repay what I owe to Ruthie and Bentie for all the care they have provided me over the years.  Bless 'em.  They signed up for the wrong chick as I can put on a horrifying cancer show more than once!!!!  Still, during the debacle that was my addenocarcinoma incarceration, I wanted to show my appreciation somehow!  But, being unable to leave the house or do much of anything...what could that be?  Lovely, outspoken, and fabulous Chrissy Teigen to the rescue!  Her humor had already made me and Ruthie laugh.  Her cookbooks had rave reviews.  And, the titles were perfect for my mood:  Cravings and Hungry for More.  With Amazon at my fingertips, I purchased a copy of each for both of them, inscribing them with my feeble thanks.

Since then, we have shared many laughs just reading them!  Yes!  They are actually good reading.  CT is funny AF!!!  Though the recipes may not be in a league with Jacques Pepin (and I don't think she was aiming for that!!!) they are accessible and yummy!  We have had such fun cooking and comparing, even though we are now apart.  Here is a bit of our Chrissy Teigen cookery!

My version of CT's Banana Bread. I had a little trouble liking it at first.  Because, Banana Bread in my head, per my recipe ~ is very different.  This one is like a cake with chocolate and coconut.  Once I was able to think of it as cake, I liked it much more.  It was very moist and actually got better over time as the flavors melded.  Rose and Jamie LOVED it!!!

Ruthie's version of  CT's Carrot Coconut Soup and mine below.

Ruthie liked hers a lot. Mine was good, served here with slow roasted tomatoes, hummus and pita. However, it was made at a time when I, due to where I was in my recovery, could not tolerate the spice recommended, nor the fried shallots as a topping.  I will have to make it again, now that I can!

Roasted Cauliflower, Feta, and Orzo Salad.  I served mine warm, though I think chilled would be good as well.  Easy and yummy.

I made this in the fall when I had a bounty crop of basil in need of harvesting before frost struck. CT's Pad Grapow Chicken (basically - Basil Chicken) was simple and delicious!  Three cups of basil leaves may be difficult to attain at other times!!

THIS!!!!  Sweet Miso-butter Cod!!!!!  CT made hers with snap peas.  I used pan seared squash with a bit of miso butter added in.  The part of the recipe for miso-butter is gold!!!  It makes a lot and after using it here, I used it on baked salmon, melted on top of steaks and roasted veggies (per her Seared Steak with spicy garlic-miso butter and same skillet Asparagus)!  IT. IS. SOOOOOOOOOOOOOOO. GOOD!!!!!!!!!!!!

Cheesy Spicy Breakfast Hash by Ruthie.  She made this (as well as CT's Spicy Italian Sausage Meatloaf) for her guys and reports both were big hits!  (Even though she forgot to top the hash with cheese!!!!!  NOW if something is good WITHOUT the cheese?  That's seriously GOOD!!!!)

I love polenta (or grits...if you prefer!!!)!  But man!  CT's Cheesy Polenta with Mushrooms kicks it up a notch!!!

My version of Ron's Hobo Burger Dinners.  They were easy, tasty and fun.  Would be great for kids.  Also, another reason to love Chrissy Teigen.  She included her family - kids, dogs, father, husband, and mom - in both her books. She is a wonder at keeping it real.  Nice!

Though there are no photos to go with, I've also made CT's Sesame Salmon Soba Salad, Sesame Chicken Noodles, and her Baked Pasta Alla Norma with Mozzarella Bombs.  All were good, though B said he liked my Dan Dan Noodles and Pasta Bake better than the last two, but he is rather prejudiced.  All in all, the recipes have been dependable and delicious.  I still have plenty I want to try.  In particular - CT's Dutch Baby Pancake, French Toast Casserole, Everything Bagel Cream Cheese Breakfast Bake, Cobb Salad, Roasted Carrot and Avocado Salad with Lime Dressing, Jalapeno Parmesan Crusted Grilled Cheese, Lemony Arugula Spaghetti Cacio e Pepe, Tom Yum Noodles, Pepper's Pork-stuffed Cucumber Soup (Yep. Even Julia Child professed the wonder of cooked cukes!!!), Frito Pie, Thai Fishcakes, Sh*t on Toast ~ and there's more!  I better get cooking!!

Thanks, Bentie and Ruthie.  Really.  Even though no words or recipes are sufficient to express what I feel; I love you. - cess

Grateful....

Grateful to be here.  Grateful for one more spring with dear ones.

Hope springs eternal.  May these early spring blossoms, with their promise of warm sunny days to come, brighten your day and lighten your load. ~ love, les

HDAC6 as a way to decrease immunosuppression in melanoma patients...

Researchers have been looking at, and I've reported on their research, regarding HDAC inhibitors for some time.  Initially, they were considered as something that could be added to targeted therapy in order to prevent, delay, or overcome resistance to BRAF inhibitors.  It has also been postulated that combining HDAC inhibitors with immunotherapy could increase the effectiveness of that therapy by making melanoma cells more sensitive to it.  Entinostat and Ricolinostat are two such HDAC inhibitors.

Now there's this:

HDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics.  Laino, Betts, Veerapathran…Weber, et al. J Immunother Cancer. 2019 Feb 6.

Therapies targeting anti-tumor T-cell responses have proven successful in the treatment of a variety of malignancies. However, as most patients still fail to respond, approaches to augment immunotherapeutic efficacy are needed. Here, we investigated the ability of histone deacetylase 6 (HDAC6)-selective inhibitors to decrease immunosuppression and enhance immune function of melanoma patient T-cells in ex vivo cultures.  T-cells were harvested from peripheral blood or tumor biopsies of metastatic melanoma patients and cultured in the presence of pan-, class-specific or class-selective histone deacetylase (HDAC) inhibitors. Changes in cytokine production were evaluated by Luminex and intracellular flow cytometry staining. Expression of surface markers, transcription factors, protein phosphorylation, and cell viability were assessed by flow cytometry. Changes in chromatin structure were determined by ATAC-seq.

T-cell viability was impaired with low doses of pan-HDAC inhibitors but not with specific or selective HDAC inhibitors. The HDAC6-selective inhibitors ACY-1215 (ricolinostat) and ACY-241 (citarinostat) decreased Th2 cytokine production (i.e. IL-4, IL-5, IL-6, IL-10 and IL-13). Expansion of peripheral blood T-cells from melanoma patients in the presence of these inhibitors resulted in downregulation of the Th2 transcription factor GATA3, upregulation of the Th1 transcription factor T-BET, accumulation of central memory phenotype T-cells (CD45RA-CD45RO + CD62L + CCR7+), reduced exhaustion-associated phenotypes (i.e. TIM3 + LAG3 + PD1+ and EOMES+PD1+), and enhanced killing in mixed lymphocyte reactions. The frequency, FOXP3 expression, and suppressive function of T regulatory cells (Tregs) were decreased after exposure to ACY-1215 or ACY-241. Higher frequencies of T-cells expressing CD107a + IFNγ+ and central memory markers were observed in melanoma tumor-infiltrating lymphocytes (TIL), which persisted after drug removal and further expansion. After ACY-1215 treatment, increased chromatin accessibility was observed in regions associated with T-cell effector function and memory phenotypes, while condensed chromatin was found in regions encoding the mTOR downstream molecules AKT, SGK1 and S6K. Decreased phosphorylation of these proteins was observed in ACY-1215 and ACY-241-treated T-cells. AKT- and SGK1-specific inhibition recapitulated the increase in central memory frequency and decrease in IL-4 production, respectively, similar to the observed effects of HDAC6-selective inhibition.

HDAC6-selective inhibitors augmented melanoma patient T-cell immune properties, providing a rationale for translational investigation assessing their potential clinical efficacy.

Step by step!  Hopefully these inhibitors will benefit real live melanoma ratties very soon!!!  - c

Sew Chaotically! ~ Nikko, from True Bias, X 2!!!!

Life has gone a little cray cray at the moment...as she is wont to do...so I don't have the best pics for this post, but wanted to share as well as create a small diversion for myself!!!  I love a nice turtleneck and had wanted to stitch up a Nikko from True Bias for some time!  So, I did!!!  I made the little sleeveless grey version first.  It is PERFECT!  Size 8.  No mods.  It fits pretty closely, which is what I wanted for this one.  Be careful of the neck opening and the stretch your fabric provides.  I don't think I have a particularly big head (HA!) and it's a little snug!  Just say'n!!!

My next version is made up in a particularly nice knit I picked up in Nashville from the Textile Fabric Store.  I wanted a looser fit for this one so used the size 10 with no modifications.

It's an easy piece to style lots of ways!

And kinda fun when your top matches multiple rooms in your home!!!  

Wishing everyone a great weekend.  Sew Chaotically!!! ~ les

Sew Chaotically! ~ a little gown (Needed wardrobe element and scrap busting!!!!)

After my recent incarceration and having a great time making things for my girl, I have spent a bit of time organizing my fabric stash and remnants, deciding upon ways to reduce waste and utilize 'scraps', and ultimately what my wardrobe really needs.  As I mentioned in my last post, upcoming sewing projects will address a lack of pj's and play clothes.  Despite the attire my recent incarceration (5 months spent enduring two abdominal surgeries and chemo for ex-goblet cell appendiceal addenocarcinoma) forced upon me, I do not usually spend my days in athleisure or loungewear!!  (Not judging, just say'n!!!)  In fact, the things I have been forced into wearing for the past bit (tank tops and elastic waist knit pants with a robe or sweater) now spark actual anger when I spy them (quite the antithesis to the joy Marie Kondo calls for as a reaction to possessions we choose to maintain!!) and are completely worn out given their non-stop rotation!  SEW!!!  I am going to make pretty, useful things to rest and play in!!!!  (With the understanding that most of the "play clothes" will lend themselves to being dressed up or down and other more fabulous items may be thrown in as my whims and fancy desires!!!  HA!)  As a start, that ticks ALL the boxes, I made a little gown using a leftover bit from this Toaster Sweater and a pattern I already owned, but had not stitched up!

Gotta say.  The pattern made up even better than expected!  Straight size 12.  No changes except more gathers (ie more fabric taken in) via the elastic under the bust.  I made it as long as my fabric scraps allowed, adding the strip at the bottom, which I left simply as a serged edge, to attain the greatest length possible.

I am pleased!!  I literally used every smidge of some very nice material, made a wearable muslin from an untried pattern in my stash, and have a pretty, comfy nightie that I don't look at with loathing!!!  YAY! - Sew Chaotically!!! ~ les