Sew Chaotically! - Sew bots????!!!

B shared this video from the Wall Street Journal with me today:  WSJ series - Moving upstream: How sewing robots may put humans out of work

The sewing and textile industry has always been an amazing utilitarian and artistic venture while simultaneously being one that often abuses, underpays, and mistreats its employees, who are, and have historically been, predominantly women.  In New York City in 1911, 145 workers died in the The Triangle Shirtwaist Fire ~ a sweatshop that employed about 600, mostly non-English speakers, who worked 12 hours a day, 7 days a week, for $15.000 per week.  There were 4 elevators in the building; only one worked.  The fire escape was narrow and dilapidated.  One exit door was locked and the other opened inwardly.  When the fire started in a box of rags, the manager discovered the fire hose was rotten and the water valve rusted shut.

Sadly, I'm not sure 'we've come a long way baby'!  Although the fashion industry has provided families, through the employment of the women in them, a wage that lifts them out of the most devastating poverty, these women remain frequent victims of demanding work quotas in poor working conditions for very little pay.  They are often illiterate, lacking in education generally and math in particular.  As the video at the top notes, today in Bangladesh, these women are lucky to make $164.00 per month.  As if that were not enough, here come the machines and bots - machines that can knit a sweater for Zara faster than human hands.  The video details machines used in a Japanese prison where workers with as little as one day of training create guard uniforms.  In Arkansas and Japan completely automated bots are being developed to sew a variety of garments.  Check out the video to see how machines sew perfect pockets and distress your latest jeans!!!

MY Creative Corner!!!

Sew-bots!!!  Part of me LOVES this!!!  And, it is a fact, that we home sewists wouldn't be making OUR garments without OUR machines!!!  My sewing improved in gigantic leaps when B got me Bernie and Sergie!!! But, this needn't be a one sum game!  Why can't we utilize the best that  machines provide while keeping the human touch?

Afghan #9 zillion and one for a special baby on the way!!!

Here's the thing.  In 2018, why DO we have illiterate people on the planet?  Why do we have people in poverty?  Children with insufficient food?  Girls (as well as boys) with NO opportunity for a basic education?  I actually know some of the answers.  Basic greed and power covers most of it!!!  So, I guess the better question is:  Why do WE ALLOW this circumstance?????  And folks...it IS a "WE"!  You and ME!!!  If the human brain and spirit can invent self driving cars, shoot rockets (and cars ~ what a waste of a Tesla!!!!!!!!!!!!!) into space, along with machines that can create garments with no need for human hands, we can feed and educate the world's people!  This kind of entrepreneurship, creative genius, and absolute brilliance can do SEW much more!!!  There really is no reason for the women of Bangladesh to be impoverished or left behind as automation, as it surely will, moves forward!!!

We can do better!  Let's start now!!! Sew and live chaotically! ~ les 

Simple blood tests that tell us how melanoma patients are responding to therapy and identify their disease in the first place....AGAIN!!!!

Yep.  It's me again, Margaret.  I'm still yelling about simple blood draws that can provide critical information related to the diagnosis of, feasibility of treatment for, response to treatment, and prognosis generally in melanoma patients!  Just last week I posted this:  More blood tests to determine prognosis as well as response to therapy in melanoma patients!!!

Now, there's this....

Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma. Takeuchi, Tanemura, Tada, et al.  Int Immunol. 2017 Dec 23.

Cancer immunotherapy that blocks immune checkpoint molecules, such as PD-1/PD-L1, unleashes dysfunctional antitumor T-cell responses and has durable clinical benefits in various types of cancers. Yet its clinical efficacy is limited to a small proportion of patients, highlighting the need for identifying biomarkers that can predict the clinical response by exploring antitumor responses crucial for tumor regression. Here we explored T-cell responses associated with clinical benefits using peripheral blood mononuclear cells (PBMCs) from patients with malignant melanoma treated with anti-PD-1 monoclonal antibody (mAb). Pre- and post-treatment samples were collected from two different cohorts (discovery set and validation set) and subjected to mass cytometry assays that measured the expression levels of 35 proteins. Screening by high dimensional clustering in the discovery set identified increases in three micro-clusters of CD4+ T cells, a subset of central memory CD4+ T cells harboring CD27+FAS-CD45RA-CCR7+ phenotype, after treatment in long-term survivors, but not in non-responders. The same increase was also observed in clinical responders in the validation set. We propose that increases in this subset of central memory CD4+ T cells in peripheral blood can be potentially used as a predictor of clinical response to PD-1 blockade therapy in patients with malignant melanoma.

Here researchers looked at the blood of folks before and after patients with melanoma were treated with anti-PD-1.  They found that a particular type of CD4+ T cell increased in long term survivors and clinical responders...but NOT in non-responders.

That seems pretty straight forward to me!  But, there's more....

A high neutrophil to lymphocyte ratio prior to BRAF inhibitor treatment is a predictor of poor progression-free survival in patients with metastatic melanoma. Finon, Zaragoza, Maillard, et al. Eur J Dermatol. 2018 Jan 16.

Some studies have shown that a high neutrophil/lymphocyte ratio (NLR) greater than or = to 4 before initiating ipilimumab treatment is an independent prognostic indicator of poor survival in patients with metastatic melanoma (MM). To determine whether the NLR before starting BRAF inhibitor (BRAFi) treatment in patients with (MM) is associated with progression-free survival (PFS). This retrospective study included 49 patients consecutively receiving BRAFi for MM between July 2012 and December 2014. Cox proportional hazards regression was used to analyse the relationship between NLR and other factors, such as lactate dehydrogenase (LDH), performance status, BRAFi as first- or second-line therapy, and corticosteroid intake with PFS. The NLR before starting BRAFi was significantly associated with PFS based on univariate analysis and multivariate analysis adjusted for potential confounding factors, such as LDH activity, ulceration, performance status, first-line therapy, and corticosteroid intake. A high NLR (continuous variable) was associated with short PFS, and NLR greater than or = to 4 was associated with shorter PFS . Corticosteroid intake was not associated with short PFS based on multivariate analysis. An NLR greater than 4, before starting BRAFi treatment, is an independent prognostic indicator of poor progression-free survival.

SO.....again ~ folks with a high NLR (greater than or = to 4) did worse!!!  This is NOT news people.  I've been yelling about this since 2015!!!

That fact was valid when the NLR was tested in folks without metastatic disease ~  Neutrophil-to-lymphocyte ratios as a predictor of death from melanoma in patients with NONmetastatic disease
That fact was valid when the NLR was examined in regard to ipi (as noted in the above article) ~  Neutrophils as a prognostic predictor in patients trated with ipi/Yervoy
That fact was valid when first postulated in 2015 ~  Lab values that may predict response to Ipi/Yervoy????

Do we really need to examine that any further???  There is also this...

Development and validation of a plasma-based melanoma biomarker suitable for clinical use.  Van, Lincoln, Van Laar.  Br J Cancer. 2018 Jan 23.

In Australia, more money is spent on skin cancer than any other malignancy. Despite this, the mortality rate of melanoma, the deadliest form, has steadily increased over the past 50 years. Diagnostic imprecision and a lack of complimentary molecular biomarkers are partially responsible for this lack of progress.

Whole-microRNAome profiling was performed on plasma samples from 32 patients with histologically confirmed melanoma and 16 normal controls. A classification algorithm was trained on these data and independently validated on multiple previously published microRNA data sets, representing (i) melanoma patient- and normal-blood, (ii) melanoma and nevi biopsy tissue, and (iii) cell lines and purified exosomes.

38 circulating microRNAs had biologically and statistically significant differences between melanoma and normal plasma samples (MEL38). A support vector machine algorithm, trained on these markers, showed strong independent classification accuracy (AUC 0.79-0.94). A majority of MEL38 genes have been previously associated with melanoma and are known regulators of angiogenesis, metastasis, tumour suppression, and treatment resistance.

MEL38 exhibits disease state specificity and robustness to platform and specimen-type variation. It has potential to become an objective diagnostic biomarker and improve the precision and accuracy of melanoma detection and monitoring.

Here folks looked at blood samples for microRNA whose presence helped define the difference between melanoma and normal plasma.  

I have endless posts regarding the examination of tumor DNA in the blood of melanoma patients, allowing for the identification of disease, BRAF status, progression, response, etc.  Earlier this month, I posted this:  Circulating tumor DNA to help differentiate true progression of melanoma vs pseudoprogression in patients treated with anti-PD-1  Here are about a zillion additional posts:  Circulating melanoma DNA

Really people!  Can someone not do a definitive study on a larger scale...rather than piecemeal this and that....without sharing data...to come up with a valid and specific melanoma panel???  We have simple lipid panels that help guide heart health.  We have lab draws and tests that help diagnosis and monitor diabetes.  No set of labs is an absolute for ANYTHING.  BUT!!!!  They are incredibly important tools in diagnosing, treating and managing a wide variety of disease processes.  They can do that for melanoma, too!!!   We have learned that we can look at T cells, other basic blood cells, tumor DNA, RNA, all sorts of bits and bobs....floating in the blood of patients with melanoma, to provide meaningful information that could allow melanoma patients and their doctors a mechanism for making better choices in their treatment and care.

Radiologic scans expose us to radiation, "find" lots of red herrings, and are a huge financial burden.  They also have limits regarding what they can see.  Sub-centimeter tumors, not to mention little demon melanoma cells floating about, are not visualized.  Additionally, imaging studies are cumbersome and have a built in time lag that can delay needed therapy or a change in current therapy as patients wait for "their next scan" to be compared to a prior one in order to define disease status.  Determining pathology from tumor samples is often confusing.  I had to have my initial slides examined by 3 pathologists to gain consensus that I was in fact dealing with melanoma.  Folks need and deserve answers. A basic algorithim that incorporates all forms of investigation including blood markers, nuclear, radiographic, and tissue examination needs to be established for melanoma. NOW!!!

Seriously..NOW!!! - c

Living Chaotically!!!!

I know you will be surprised to learn that I've been running about chaotically!!!  Working a bit extra.  Getting back into shape after my sicknesses!!!  How can things slide so quickly?!  Oh, well.  I've pretty much returned to normal with my runs, elliptical, and workouts with Roo.

Brent and I prepped our garden beds.  Seeded our early spring garden with radishes, sweet peas, broccoli, various lettuces, chard, and carrots!  We've also made plans for adding another shrub/flower bed in the front.

I know, I know!!!  They are itty bitty!!  But they're there!!!  I've learned to enjoy what I can when I can!!!!

I've scrubbed all the window frames free of the gunk they magically accumulate over winter. Tidied closets.  Gone through clothes.  Caught up the ironing.  Had my teeth cleaned.  The cheek lesion my hygienist found (Story here:  October 2017: Trick or Treat!!!!) and that subsequent evaluations by my local oncologist and ENT determined to be nothing/vitiligo on a scar from all my prior oral lesions that were side effects of my nivo - remains about the same.  Nothing else to discuss.  Boring is GOOD!!!

My Lenten Roses have begun to peek out.  Such funny little flowers!!!

Recently I've had difficulty getting my glasses clean!  They seemed to have a film that I just couldn't remove.  Suddenly, a thought came to me.  What if the problem is not with the glasses???  I crack myself up!!!!  I had my eyes examined.  And....uh, yeah.  I need a new scrip.  Nothing bad.  Just a bit older.  Another year that I will embrace happily!!! I'll really embrace better vision when my new glasses arrive in a couple of weeks!!!

I whipped up some spice blends for Roo and J as well as myself!

I just love this book!  It has great information on spices generally, fabulous recipes for spice mixtures, and additional recipes using them in dishes.  YUM!!!

I have a zillion exciting sewing projects in process and in my head.  I am working with B on planning some fun trips.  We miss our Karmie every day.  Silly little bugger!!!  I am enjoying rediscovering my flower friends as spring seems to have sprung here on the mountain.  In case she has not yet come to your part of the world, here's a bouquet for you:

Daffy-down-dilly has just come to town, with a yellow petticoat and a pretty green gown!
Enjoy chaotically!!! - love, les

More blood tests to determine prognosis as well as response to therapy in melanoma patients!!!

It is becoming more and more clear (at least to me!!!!!!!!!) that there are all sorts of ways of looking at blood markers in order to diagnose, predict progression and response, as well as evaluate response to a particular treatment in melanoma patients.  Here is my latest post with a zillion links within:  Circulating tumor DNA to help differentiate true progression of melanoma vs pseudoprogression in patients treated with anti-PD-1  Now, there's this ~

Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients. Zager, Gastman, Leachman, et al.  BMC Cancer. 2018 Feb 5.

The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients.

This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival.
The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively. The GEP was a significant predictor of RFS and DMFS in univariate analysis , along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status . GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate .

The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.

Think how great this sort of information would be when trying to determine whether or not to utilize adjuvant therapy!!!

But, that's not all!  There's also this ~

Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy.  Hong, Sullivan, Kalinich, et al.  Proc Natl Acad Sci U S A. 2018 Feb 16.

A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival and overall survival. Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.

Wouldn't it be great to know where you stand 7 weeks into therapy?  You wouldn't waste time (and in melanoma world that "time" can make all the difference!!!) with a therapy that is not working for you!!!

Blood draws with more detailed info than repeated radiological studies!!!  C'mon man!!!  Let's get some consensus and make these tests available for patients in need! - c

Rechallenge with BRAF/MEK combo in melanoma

For BRAF positive melanoma patients, targeted therapy with a BRAF inhibitor combined with a MEK inhibitor can have amazing results in the destruction of melanoma!  Response rates are around 70-80%!!  While there are a few exceptions, the problem with this targeted therapy is that the benefit often evaporates around 6-9 months, with sinister melanoma developing the ability to work-around the treatment.  These peeps then go on to other treatments.  Sometimes those work, sometimes they don't.  If they don't, will taking BRAF/MEK again work?????

Now, there's this:   

Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study. Valpione, Carlino, Mangana, et al. Eur J Cancer. 2018 Jan 19.

Most metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy.

One hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated.

The median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease (SD) 24% and progressive disease 30%, 4% missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites , lactic dehydrogenase, while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone.

Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.

In this study, 116 peeps who had taken BRAFi (a BRAF/MEK combo) for an average of 9.4 months stopped taking it for a variety of reasons ~ and had roughly 8 months of:  immunotherapy (72%), other treatment (17%) and drug holiday (11%).  They were then rechallenged with a BRAF/MEK combo.  Response rate for the rechallenge was 43% with 3% attaining a complete response, 39% a partial response and 24% gaining stable disease, although 30% had progressive disease and 4% were apparently lost to follow-up.  Of the 83 peeps who stopped BRAFi initially due to disease progression, 31 responded to the rechallenge - 30 with a partial response and 1 with a complete response.  Median OS from BRAFi retreatment was 9.8 months and PFS was 5 months.

Given the results of this study, the answer to the initial question I posed, is:  YES, a rechallenge with BRAF/MEK can work with a response rate of about 43% generally and 37% in those who progressed on BRAFi the first go round.  Response rates are not as high nor as complete as those attained with the initial treatment....but....they are there!!! Repeating treatment with BRAF/MEK is certainly an option in kicking melanoma in the teeth a bit, while seeking more effective, durable treatment.

It's something.  Thanks, ratties.  - c

B's Karma! 18 years my sweet Karmie! You were awesome!!!

If you've read this blog for 10 minutes, it's pretty clear that B spoils me rotten.  However, every once in a while, something happens to his brain.  About 18 years ago, despite having my 90 pound, pound puppy Ruff Ruff (Yes.  He really was from the pound, some thick lab/shepherd mix, named by a 4 year old.) in the back yard, I told Bent that it would be super awesome if we got an inside puppy.  He looked at me....and said...."No!"  What the????  Not, "Okay, baby.  We'll see."  Or, "Really, sweetie?  Well, we'll think about it."  He. Said. NO!!!!!!!!!!!!!  Well!!!!  I didn't speak to him for days.  But, then, on a cold, rainy November morning in 2000, B brings me a cup of coffee in bed (What a jerk!!  Right????) and says, "There's a puppy outside."  I think my response was something like, "Kiss my ass!"  He just looked at me sadly and said, "No.  Really.  There's a puppy outside."  Feeling that I am being tricked somehow...I looked out the front door.  Sure enough.  There was a beagle-esq, shivering, pup. Foot pads, cut and bloody.  Skinny.  Trying to stay under the eave, out of the rain.  Well.  In about two seconds, he was cuddled up in my robe. Scrubbed free of his fleas and such.  And welcomed INSIDE!  A new puppy (somewhere between 6 and 16 months per the vet) named....KARMA!  B's. Not mine.  He was the sweetest.  Never peed or pooped in the house (until recently).  LOOOOVED the kids.  Would run and bite Fred on the bootie on command.  Would lie like a contented snoring unconscious thing on his pillow. THEN! You see that the toast or chicken or cake is eaten - the shoe is destroyed - the potted plant is UN and dirt is every where!  You look back!  The Karm is still snoring on his pillow!  HOW did this happen????  He would look at you sweetly and say, "Wasn't me!"  He was my worst trained dog ever.  He never "came" or "heeled".  But, he never barked.  He LOOOOVED Ruff Ruff and later Zeno. He wanted so much to run with the big dogs.  The only noise he ever made was to yoddle happily when on a walk with all his peeps and the big dog!  On meeting him, Ruff looked up at me and said, "Really, mom?  We have to keep him?  I could do away with this THING in a single bite?!"  My Ruff WAS well trained and believed me when I said, "Yes.  He needs a home."

Happy with his Freddo!

Lining his "dead animals" up on the window sill!  B loved this concept!!  I often walked into the kitchen area to find B's socks and undies lined up there as well!!!!  (To tease Brent I would accuse him of doing it!  But, the reality was that every morning the Karmster would skitter on two doggie wheels into the bathroom where B would be getting ready for work and steal all the random clothing items he could - clean, dirty, didn't matter!  Dashing off, he would carefully place them on 'his' window sill, then zoom back for more!!)

The fierce beastie!!!

Karm and Roo!

You see Zeno staying with his peeps and Karma just going his own way????

The boy.....

...and his dog.

He was always a good walking buddy and LOVED all my makes!!!

The past year was tricky for Karm.  He lost his hearing and vision.  It didn't really slow him down.  We adjusted.  We didn't let him go too far afield on his leash so that he wouldn't crash into something.  He knew his way around the house on his own.  He liked nothing better than sitting on his pillow between both our feet, as we sat on the couch and talked or watched TV.  However, over the past two weeks eating and walking were not things he was really able to do.  He remained sweet and docile to the end.  You were one of a kind, dear Karm.  Thanks for wandering into our lives.  Thanks for all the laughs.  Thanks for being my pillow when I felt unwell with my treatments.  Pups.  Family.  We will all miss your sweetness.  - les

For J and F, Ed, Stevie and all my other more northern peeps!!!

SPRING is sprung!!!  She's coming!  I know you may still be snow blow'n....but she is on her way.  Here is a first taste of mine...

Maybe I should eat it?  Or make it into a paste?  Everything Cures Melanoma!!! (And yes, we're up to installment #9 - with no actual cure!)  I think I'll just love it!

She may not look like much right this minute (speckled leaf to the right) but I am pleased to see her.  She is one of two trout lilies I have planted along the edge of my creek.  They have yet to bloom, but they have come back every year. 

Here's one in Cades Cove doing her thing!!!

With all the nasty that life and weirdos and melanoma can dish out - it is still a Wonderful World (Thanks, Louis!)!

If you want a bigger and even more beautiful look at SPRING in what I also consider "my backyard" ~ check this out:  April in Cades Cove, 2015.

"I see trees of green, red roses, too.   I see friends shaking hands, saying 'How do you do?'  They're really saying, 'I love you!'"     ~ Oh, YES!!!! - les

Circulating tumor DNA to help differentiate true progression of melanoma vs pseudoprogression in patients treated with anti-PD-1

I've been yelling for some time about the need to develop, refine and put into practice valid, reliable blood assays....whether they are measuring circulating DNA, tumor cells, various other tumor makers, white blood cells, any other floating bits and bobs...in order to diagnosis melanoma, determine the most effective treatment, and recognize progression and/or effectiveness of that treatment.  Here is a link to a zillion of those reports/rants:  Blood assays, tumor markers, circulating DNA, you name it!!!! 

In fact, the report below is a follow-up report and specific look at pseudoprogression from this study:  2017: Circulating DNA predicts response to anti-PD1

Now, there's this -

Association Between Circulating Tumor DNA and Pseudoprogression in Patients With Metastatic Melanoma Treated With Anti-Programmed Cell Death 1 Antibodies.Lee, Long, Menzies, et al. JAMA Oncol. 2018 Feb 8.  

Longitudinal circulating tumor DNA (ctDNA) has been shown to predict response and survival in patients with metastatic melanoma treated with anti-programmed cell death 1 (PD-1) antibodies. Pseudoprogression, defined as radiologic finding of disease progression prior to response, has been a challenge to clinicians.

To establish whether ctDNA at baseline and up to week 12 of treatment can differentiate between the radiologic findings of pseudoprogression and true progression in patients with metastatic melanoma.

This explorative biomarker study examined circulating BRAF and NRAS mutations in a cohort of 125 patients with melanoma receiving PD-1 antibodies alone or in combination with ipilimumab between July 3, 2014, and May 24, 2016. Pseudoprogression was defined retrospectively as radiologic progression not confirmed as progressive disease at the next radiologic assessment. Plasma samples of ctDNA at baseline and while receiving treatment were taken for analysis prospectively over the first 12 weeks of treatment. Favorable ctDNA profile (undetectable ctDNA at baseline or detectable ctDNA at baseline followed by greater than 10-fold decrease) and unfavorable ctDNA profile (detectable ctDNA at baseline that remained stable or increased) were correlated with response and prognosis.

Early differentiation of pseudoprogression from true progression using longitudinal ctDNA profile.

According to guidelines by Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease occurred in 29 of the 125 patients (23.2%). Of the 29 patients, 17 (59%) were 65 years or younger, 18 (62%) were men, 9 (31%) had pseudoprogression, and 20 (69%) had true progression. Of the 9 patients (7%) with confirmed pseudoprogression, all patients had a favorable ctDNA profile. At a median follow-up of 110 weeks, 7 of 9 patients (78%) were alive. All but 2 patients with true progression had an unfavorable ctDNA profile. Sensitivity of ctDNA for predicting pseudoprogression was 90% and specificity was 100%. The 1-year survival for patients with RECIST-defined progressive disease and favorable ctDNA was 82% vs 39% for unfavorable ctDNA. Overall survival was longer in patients with a partial response (54 of 125 patients [43%]) compared with patients with progressive disease and a favorable ctDNA profile (11 of 125 patients [9%]).

The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies. Results of this blood test performed at regular intervals during systemic treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response and survival.

Here researchers looked at 125 melanoma patients with BRAF and NRAS mutations treated with anti-PD-1 alone or in combination with ipi between July 2014 and May 2016.  They drew their blood before and during the first 12 weeks of their treatment and correlated those findings with the patient's response and prognosis.  Per the RECIST scale, progressive disease occurred in 29 of the 125.  9 had pseudoprogression and 20 had real progression.  "All but 2 of the patients with true progression had an unfavorable ctDNA profile.  Sensitivity of ctDNA for predicting pseudoprogression was 90% and specificity was 100%."  The 1 year survival for the folks with RECIST defined progression but WITH the favorable blood test ctDNA was 82%, while for folks with an unfavorable ctDNA it was only 39%.  "The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies."

I think we've yammered about this stuff enough.  Consistent, available, defined blood assays need to be made readily available for melanoma patients!!!! C'mon man!!!! - c

One Hell of a day! And, yes. Fredda Branyon is STILL a criminal!!! So is Mathew Anderson, Kurt Adams and Mathew Adams in Tampa!!!

Okay. I have the best family and friends EVER!!!  My dear sweet love, D, taught my husband in college when B was only 18+.  Need I say more???  This man (D) is clearly a saint!  I've been dealing with B after maturation at age 40!  Girl!  It's been real!!!  D was not only B's professor but mentor.  Paths diverged, but realigned when they found each other again 20+ years ago.  Since then we have been forever bonded.  We are hiking buddies.  We are parents and grandparents.  We are dinner companions. D sat with B through my surgeries.  D takes care of my children, even though they are now 25 and 27. Hell!  D takes care of ME!!!  WE are FAMILY!!!  Today a fucking asshole scammed my dear D.  Calling him...saying, "Hey, this is your grandson!"  To which D responded, "What?"  But, then he assumed it was my son.  In the end scammer asshole said my son, D's dear grandson, was in jail due to unfortunate circumstances in Tampa, Florida and needed $1,485.00 in order to make bail.  My dear sweet friend, went as fast as he could to the nearest Moneygram office and sent the money.  This ass first called posing as my son, then, as soon as it sounded as though D would help, he called again - posing as a person (Matthew Anderson) from the Public Defender's Office in Tampa who needed the money sent to Kurt Adams in the office of Bail Bonds Roche at 1906 Orient Road, Tampa, Fla.  Kurt Adams took the money. 

Not only did he take the money....he called dear D back later that afternoon.  Shockingly, he needed more money to settle the entire situation.  Well, dear D didn't have that money.  So, he came over.  Needless to say, he had promised his grandson that he wouldn't tell us of all the difficulties...but when the funds were such that he couldn't meet the need...he felt horrible...but came to tell us.  Well! We called our son.  No, he was not in Tampa.  And, No!  None of the things alleged had happened!!!!  But, we went to town on Matthew Anderson/Kurt Adams/Matthew Adams!!!  (And, I am not done!!!)

A quick google of the number:  1-800-388-6514 (Please call it!  One thousand times.  Over and over.  Leave a message that you are ready to wire money for your dear one!!!!) shows that many folks have been scammed in a similar way.  See this post:  https://www.facebook.com/celeste.morris.140 where I added to the message the Lucas County Sheriff's Office has put out.

Thankfully, Moneygram....somehow, someway....despite paying out the initial sum....figured out this asshole is a scammer.  They are to refund my dear sweet D his money.  But....I am not done!  I will be contacting the Hillsborough County Sheriff's Department in the morning.  I have already reported the crime here in TN.  I have let the Bail Bond Company know that their name and address are being used by an ass.  I am not done!  Be ware and help me if you can.  I HATE BULLIES!!!  And thieves.  And liars!!!!!!!!!!!!!!!!!!!!!!!!

On that topic....Fredda Branyon.  Remember her????  Check out this post if you don't:  Quack Watch!!! - Jerks who try to take advantage of the word "cancer"! And this one:  Jenny Hudgeson, Kim Burns, and Fredda Branyon...different or the same????  This bitch and her minions (or just herself with poor English and weirdness) posted on MY blog!!!  Then, with a little research, I discovered she was posting on any blog with "cancer" in the title!!!!!!  What a horrible person!!!  As if that was not enough, I learned this:  Stem Cell Smuggler Pleads Guilty

Basically, it says this: 

A former Arizona laboratory owner has pleaded guilty to selling unapproved stem cells across state lines.  Fredda Branyon, the former owner of Global Laboratories in Scottsdale, AZ, faces up to three years in jail and up to $10,000 in fines. Appearing before a US district judge on August 18, Branyon admitted that in 2009 her company sold stem cells for non-research purposes without FDA approval.

Specifically, she admitted to selling 183 vials of stem cells to an individual in Brownsville, TX on 27 separate occasions between April 2009 and February 2010 for approximately $300,000. This individual then treated patients suffering from autoimmune diseases with these stems cells.

The stem cells were not created under FDA guidelines or in an FDA-approved facility. Instead, Branyon created the stem cells from the umbilical cord tissue purchased from a Del Rio, Texas midwife. Because Branyon did not have an experience creating stem cells, she hired a Charleston, SC medical school professor to assist her.

“It’s a real disservice to people who are really trying hard to follow rules, and perhaps overly strict rules because of the misinterpretations of what stem cells are. To do something like that just makes it harder and harder for those therapies to become actualized,” said Broad Institute stem cell researcher John Rinn.

In 2009, Branyon announced that her Branyon Integrative Medical Group (BIMG) would perform a study on the treatment of HIV-related illness using umbilical cord-derived stem cells. The study was designed as a six-month program to be overseen by Mexican physician Edgar Payan Arechiga. It is not known if this study was actually conducted. The BIMG, formerly known as the New Hope Medical Center, was founded by Branyon to offer alternative treatments for patients suffering from cancer and other chronic illnesses.

“It’s just too easy to make money off of sick people, and some of these [stem cell] clinics are taking real advantage,” says stem cell clinic watchdog Barbara Hanson. After a bad experience in a Tijuana stem cell clinic that promised to cure Hanson and her friend’s chronic obstructive pulmonary disease (COPD), the two women co-founded the online forum Stem Cell Pioneers in 2007. The forum gives patients interested in stem cell therapies a place to share information related to stem cell treatments, doctors, clinics, and results.

In 2007, Hanson posted information on the forum about Branyon’s background, pointing out that Branyon was not an accredited doctor in the US. At that time, Branyon wrote in an e-mail to Hanson, “Because of pulling in many many types of treatments from around the world (some not FDA approved) for other MDs and DOs I decided not to become licensed. I never lost a license because I never had one to loose [sic]. With the type of research that I have donated my life to, I could in no way have done it with a license.”

So many fucking assholes!!!!!!!!!!!!!!!!!!!!!!!!!!  You make money off of men of integrity who love their children.  You make money off desperate cancer patients.  Are you kidding me????  

But...I digress.  Fredda still thinks she is awesome.  Her doctor-less self who lied, stole, broke the law, used cancer patients....still thinks she has an audience!!!  Here is her blog:  Dr. Fredda Branyon My life's mission is to Educate people about the power of Hope   STILL calling herself a DOCTOR...no less....and hijacking HOPE!!!!!!!!!!!!!!!!!!!!

What the hell?????  I. AM. NOT. DONE!!!!!!!!!!!!!!!!!!!!!!!!!!!!!  Help me if you can.  I try to be a beacon of light.  But, I am sick of this shit!!!

Where are the people in charge???  Where are the Medical State Boards???  Arizona????  Seriously???  We got kids killing kids.  We got an orange man telling us we need to recognize kids in need of help.  I DO!!!  EVERYDAY!!  And guess what?  There are NO services!  Kids living with friends because their parents are dead, or in jail, or don't care...don't have insurance.  And even if you do have insurance....have you tried to access mental health services?  Or ANY services????  This kid was pitiful...horrible....despicable...tortured...evil...broken.  Whatever you want to call it.  Whatever it really was.  If he hadn't had a gun he couldn't have killed 17 innocent people.  PERIOD.  

My heart hurts.  My head hurts. And I have lost nothing.  But...I. AM. NOT. DONE!!!!!!! - c

Happy Valentine's Day ~ Chaotically!!!

I am absolutely, hands down, the luckiest girl in the world!!!  All because of THIS guy ~

Yes, Bentie had just about knocked his leg off hopping into place after setting the camera!  See the concern on all our faces????

He cleans up nice, doesn't he???

Is very colorful!!!

Knows how to let loose!!!

Is good in close spaces!

Does NOT like to be a hot little donkey!!

Will deal with animals that he doesn't wish to know if it makes little people happy.

Is the best son, caretaker, and friend EVER!

Is basically a BAD ASS!!!

An amazing hiking buddy!

And if all of that, and YEARS of dedicating his life to the care of children were not enough, he is out in the community daily - speaking out for the rights of children and their families to have safe, clean spaces in which to play!

Even today!  There he was, fighting for:  Air you can breathe!  Water you can trust!  Climate you can live in!  Dirt you can play in!

And to confirm that I am lucky in even more ways ~ I had a most beautiful visitor!

As well as a super fun and lovely visit from Roo this past weekend, where we made TWO fun tops.  This little Sorbetto in a crazy "CHEMISTRY" print...

...and a fun cropped LINDEN sweatshirt out of remnants of a soft moleskin scuba I recently used in a jacket and a nice black knit from a skirt for Roo to be!

And today...this sweet girl...joined me at our Barre Boot Camp workout, where she cheered me on as I managed to do ALL the push-ups, ALL the planks, and ALL the SIDE planks!!  Not easy for a person with complete lymph node dissections to each arm, with the right side sporting 9 surgical scars from that and various other melanoma messes!

All that SHOULD be enough, yes?  But, NO!!!  B made Toll House Cookies from scratch!!!  AND paired them with new indestructible metal wine glasses! (????) The cookies were delish!

Added lovely tulips to my pretty desk...

...and surprised me with beautiful art he had made just for me, which now hangs above my kitchen door!

How lovely is that????  Hope flies on dragonfly wings....

I love you Rose and Freddo!  I adore you, my Bentie!  You are my heart, on Valentine's Day and every day in between. - les

For Jubes...and the rest of us!!! An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib????

The minute B found this article he was yelling, "Oh, this might be important to Jubes!!!"  Well, I hope not!!!  Many (actually - probably most!!!) folks who take immunotherapy deal with some amount of arthralgias (joint pain).  However, my sweet Anne-Louise dealt with significant arthritis/spondylitis due to her immunotherapy treatment for melanoma!  However, after prednisone and other meds like infliximab she got her joint pain under control and threw melanoma to the curb!!  But....immune disease and side effects with immunotherapy remain a significant double decker problem. 

First....what if you already know you have an immune disease like rheumatoid arthritis?  Can you still take immunotherapy?  The short answer is YES!!!  You can!!  Here is a recent post on the subject with more links within:  Immunotherapy for melanoma with a pre-existing autoimmune disease??? YES!!! You can!
Here's another report:  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!

Second...there are the folks who didn't have arthritis or other autoimmune diseases (that they knew of) at the start of treatment...but end up with all sorts of immune related side effects caused by their immunotherapy.  What should we do with them????  Treat them!  Sometimes with a break of their immunotherapy, but with prednisone and other drugs as needed.  Right then, right there!  And, YES!!!  They can still go on to have a response and rid themselves of melanoma in the process!  (Just like Jubes!!!)  Here are related posts:  One more time: Immunosuppressive therapy to manage side effects to immunotherapy does NOT affect response! New report.
And this:  Immune related side effects from immunotherapy can and SHOULD be treated!!!!
And this:  Side effects and how to manage them in targeted and immunotherapy for melanoma
And finally...this post with a treatment algorithm for neuro side effects and links to algorithms for other immune related side effects:  Neurologic side effects to immunotherapy with treatment algorithm

Okay!  You'd probably like me to get to a point!  What if there was a drug that helped folks with their rheumatic disease AND helped get rid of their melanoma????  Well now, there's this:

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth. Hanson, Robinson, Al-Yousuf, et al.  Oncotarget. 2017 Dec 17.  

Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAF^V600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 µM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.  

In this study, researchers say that leflunomide...a drug used to treat rheumatoid arthritis...seemed to have "therapeutic value" when it was combined with vemurafenib (a BRAF inhibitor) as well as when it was combined with selumetinib (a MEK inhibitor)...in both BRAF positive and BRAF wild type patients!  So far, it seems that this is in petri dishes and real live furry ratties.  However, if this works this could be super cool for getting rid of melanoma as well as a boon for folks already dealing with arthritis...or perhaps debilitated by arthralgias due to their melanoma treatment.  

It's got a ways to go before we can get too excited.  But, I like the direction!!!  As for my dear Anne-Louise....I hope that she NEVER needs another melanoma or arthritis treatment....EVER!!!!  And...I do hope to hear her play her fiddle someday!!! 

Hang in there, ratties!  (Those that are furry and those who are not so much!) - c