Sunday, December 31, 2017

Durable responses to pembro. The 'C' word (CURE!!!!!!!!!!) used by melanoma researchers. And....HAPPY NEW YEAR!!!!

This is how to leave 2017 with a bang!!!!! We know that among melanoma patients there is a roughly 15% response rate to ipi and about a 40% response rate to anti-PD-1.  But, if you are a long will the response last?  I've been talking about "durable benefit" and melanoma treatments for years.  Being disease free for 10 minutes doesn't mean that much, now does it?  Here are some previous posts on durable responses ~
2016:  Nivolumab Shows Impressive OS in melanoma
2015:  Ipi for melanoma...the data keeps pouring in...and it's pretty good!
2014:  Review of immunotherapy and durable benefit in melanoma!!!

The authors in the 2016 Nivo paper above looked at overall and progression free survival and note: 

“These data represent the longest survival follow-up of patients who received anti–PD-1 therapy in a clinical study, and suggest durable, long-term survival with nivolumab monotherapy,” said lead investigator F. Stephen Hodi,

“In all patients, there is a plateauing, a so called tail on the curve, and it’s lasting many months to years, and about a third of patients have this long-term survival,” said Hodi. “Those who make it to 48 months, have a very good chance of surviving their disease.”

“What distinguishes immunotherapy from other forms of cancer treatment is the durability of the benefit. Those who have complete responses seem to be protected from that disease recurring,” said Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center, who moderated a press conference. “The memory and the adaptability of the immune response to pick off resistant variables is an important take-home here. These are very compelling data to suggest that this is the case.”

This article looks at the staying power of COMPLETE responses...a bit different from "response rate" which includes those with complete and partial responses...

Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. Robert, Ribas, Hamid, Daud, Wolchok...Weber...Hodi. J Clin Oncol. 2017 Dec 28.  

Purpose: Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( identifier: NCT01295827).

Patients and Methods: Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab. Eligible patients who received pembrolizumab for greater than/= to 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses.

Results:  Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of greater than/ = to 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis.

Conclusion: Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.

Basically, this report looks at folks treated with pembro who had a complete response (CR). A complete response was noted in 105 (of 655) patients treated, which turned out to be 16%.  There are a few other details, but ultimately of the 105 patients with a complete response, their disease free survival rate at 2 years was 91%.  67 of those 105 patients with a complete response opted to discontinue pembro (and have no further treatment - only observation) after they attained their complete response, and 90% of them remained disease free at 2 years.  In other words, there was little difference between the complete responders' 2 year survival, no matter if they continued their treatment beyond their CR or not.

While this durability, combined with the promise of nivo as adjuvant for Stage III and IV NED patients, as well as BRAF/MEK, nivo, pembro, and the ipi/nivo combo for folks with advanced melanoma is an excellent note on which to end 2017 ~ I am looking forward to a 2018 filled with improvements in melanoma care that include more responses overall and an even greater number of complete responses!!!

Bless you one and all!  Cheers! - love, c

Saturday, December 30, 2017

SLN biopsy. Delay of 40 days = WHAT???? (Plus some general guidelines)

While there is controversy around whether or not to do a complete lymph node dissection - with newer research indicating little to no increase in overall survival with the procedure - sentinel lymph node biopsy remains an essential part of diagnosis and thereby treatment!!!  How would you know you were Stage III (or not) if no sentinel node(s) evaluation was done after a cutaneous lesion is removed?????  How would you know what treatment and course of observation you would need to pursue????  Furthermore, insurance companies balk at covering anything!  When you don't have the argument of proof of metastasis to a node very few, if any, will cover important follow-up scans.
Here's a post covering a great deal of recent research on both SNL biopsy and CLND:

CLND - Complete lymph node dissection in melanoma - the whole shmegegge!!!!!!!!!!!

Now...there's this:

The intriguing effect of delay time to sentinel lymph node biopsy on survival: a propensity score matching study on a cohort of melanoma patients. Tejera-Vaquerizo, Descalzo-Gallego, Traves, et al. Eur J Dermatol. 2017 Sep 23. 

Time between primary melanoma excision and sentinel lymph node biopsy (SLNB) has not been sufficiently studied as an independent predictor of survival in cutaneous melanoma.

We used propensity score matching to evaluate whether early SLNB (performed  less than/= to 40 days from excisional biopsy) is associated with higher mortality in patients with cutaneous melanoma.

A retrospective cohort study at a tertiary melanoma referral centre. We included 787 consecutive patients from the melanoma database of the Instituto Valenciano de Oncología who underwent a SLNB between 1st January 2000 and 31st December 2015, of whom 350 were matched into pairs using propensity score matching. The variable of interest was the time between primary melanoma excision and SLNB (less than/= to 40 days vs greater than 40 days). The study outcomes were disease-free survival (DFS), melanoma-specific survival (MSS), and overall survival (OS).  

A delay time of 40 days or less was associated with worse DFS, and OS. Other variables associated with shorter MSS were age, tumour location and thickness, mitotic rate, and SLN status.  Early SLNB was associated with worse survival in patients with cutaneous melanoma after adjusting for classic prognostic factors. A delay time of over 40 days was not associated with higher mortality.

While this sounds a bit counter that leaving the positive node in place for 40 plus days...garners BETTER responses than removing the same node in 40 or fewer days in regard to disease free survival and overall survival.  However, the rational for this phenomenon is the idea that those positive lymph nodes are needed for the body to process the antigens in the melanoma cells that are present in the node(s) in order to facilitate the body's immune response.  If the immune response is never launched, the chance of persistent disease is greater.

Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. Wong, Fariers, Kennedy, Agarawala, et al. Ann Surg Oncol, 2017 Dec 13.

To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma.  An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma.

Nine new observational studies, two systematic reviews and an updated randomized controlled trial (RCT) of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included.
Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions less than 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or less than 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of greater than1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; greater than 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors, and details of the reference patient populations are included within the guideline.

So...not really much new here...but might be edifying for folks looking at making this decision.

Hang in there, peeps.  Melanoma-land is a crazy place.  - c

Sometimes I get tired, or lazy, or weary of beating the same old drum over and over.  But, sometimes...important topics NEED repeating, re-visiting, and re-evaluating.  Plus....2 heads are certainly better than one!  That being said, for those of you who don't follow the forum on MPIP, I am adding a discussion of this post that developed there thanks to my dear Edster. I think his points are worth bringing here, as are my thoughts about the "new" guidelines for SNLB which, though I have railed about them on this blog before, are perhaps even more pertinent at this time given the possibility of effective adjuvant care with minimal side effects.  That said, here you go:

Hi Celeste, does that journal article come in English or is it published in spainish? I have a thought about the time frame of the data, starting in 2000 and running to 2015. My thought is if they are looking at overall survival and progression free survival, you would think that the effect of adjuvant therapies and stage 4 therapies that would be available to the group in that time frame(2000-2013) were not very good and would make it hard to transfer finding to what is such a drastic land scape change, even in the last year and a half. Now, if they had data from say, MD Anderson from 2014-2016, with the better stage 4 drugs available to patients and Ipi approved in the adjuvant setting. If these observation held up then I could see the value of their study. I think that I am becoming to critical of research studies and wonder too much about alternative motives of researcher's. I had treatment on Friday #100 and there wasn't even a cake or candles or a marching band!!! I love the way that your blog makes me think and ask questions and how important it has been to so many of us,on our melanoma journey's!!! Hugs from a very cold Canadian!!!Ed

Hey Edster!
I think the questions you pose are good ones.  And as I noted in my comments...the data of better outcomes by delaying SLNB by 40+ certainly counter intuitive.  Alternatively, there has been a good deal of data noting that a delay of 1-2 months before SLNB has not adversely affected outcomes.  I had BOTH my SLNB's within 2-3 weeks of my cutaneous biopsy results back in 2003 and 2007. (Maybe that's why I progressed to Stage IV!!  Ha!  Who knows?)   In theory, one would assume that researchers took the time frame of the patient's diagnosis and treatment changes into account.  However, I can't be sure about that.  One other factor to be considered is that adjuvant treatment for NED Stage III or IV patients is a relatively new thing...and many of these peeps would not have had treatment unless they had active disease. is still an important point to think about when we know the landscape of melanoma treatment has changed so radically just since 2011.  The complete article is in English if you have a mere $39.95!  Hee hee!  
I don't think that this article is enough to change current practice...though it is something researchers should think about.  Mostly, it should be very reassuring to those who find themselves...for whatever reason...going longer than they like before having their SNLB.  I know I wanted the suckers out of there!  I  have worked with many here on this forum and via my blog going nutters about any delay, so this should help provide a bit of prospective.
For another point relative to that post...I don't really agree with the new guidelines for SNLB.  For instance, I would still not technically my first primary was only 0.61mm with no ulceration.  Yet, I had a positive node, developed a second primary 4 years later, and developed brain and lung mets 3 years after that.  NOT THAT EVERYONE DOES THIS!!!!!!!!!!!!!!!!   But, the more important point is that the positive node, took me from Stage 1b to Stage IIIa in one fell swoop.  Back then - it didn't matter very much.  There was no treatment.  TODAY, it makes a world of difference, because as you pointed out - ADJUVANT care!!!  Soooooo important and now thankfully exists and is FDA approved.
Additionally, the factors that make a difference for a thin melanoma are younger age (less than 40), mitotic rate (which folks don't really look at any more), higher Clark level, and sex.  Ultimately, guidelines are JUST guidelines.  A framework for a starting point...not the end all be all.  It remains very rare for thin melanomas to have lymph node involvement.  However, with a 5% chance of that positive node, now that we have various adjuvant treatment options...finding out if you are in that 5% makes a bigger difference.  
And as to the most important part of your comment - HAPPY 100th TREATMENT day, to you!!!!  I would totally have baked you a cake and had a Timmy with you!!  Salud!! You rock!!  Love you bunches...from a fairly cold Chatt town.  (Do I get to claim being cold if it's 34 degrees????) - c
Thanks, Edster.  This is important stuff and your attention to it makes the world a much better place for melanoma peeps!  love, c

To read more of this thread with really thought provoking comments from Janner, here's the link:  Discussion of SLNB post on MPIP

Sunday, December 24, 2017

About DAMN time!!! Opdivo approved as adjuvant for resected melanoma with lymph node involvement or metastatic disease!!!!

Even before I wrote this little story, as I was getting my last dose of Nivolumab in June of 2013, Love Potion...or Patient...#9!!!!!  which includes this history of Opdivo's development ~

Once upon a time (2005), in a land far, far away...(Japan), ONO Pharmaceutical generated ONO4538, an anti-PD1 monoclonal antibody, in research collaboration with Medarex (who called the product, MDX1106).  In 2009, the big, getting ever bigger, (? benevolent) King of the World, Bristol-Myers Squibb (BMS) acquired the rights to develop ONO4538/MDX1106/BMS936558  in North America.   In an additional agreement in 2011, BMS attained the rights to the product in the rest of the world...except Japan, Korea, and Taiwan...where ONO retained exclusive development rights and is conducting Phase II studies with ONO4538 in non small cell lung cancer and melanoma and Phase III studies in renal cell carcinoma currently.  However, no results of either of those studies can be found.  Thus began the exploration of BMS 936558 in the Americas! 

~ to as recently as this past November when I put together this post (which covers the results of the CheckMate-238 trial):  Review of adjuvant treatment in Stage III melanoma and "death knell" for ipi and interferon in that role!!!!  I have NEVER stopped SCREAMING about the obvious need to approve anti-PD-1 for the adjuvant treatment of melanoma in Stage III AND IV patients!!

Thanks to all the ratties and researchers who kept of 4 days ago - it's finally done:  FDA Approves Adjuvant Nivolumab for Melanoma

The OncLive link above notes:  "The FDA has approved nivolumab (Opdivo) as an adjuvant treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease, based on findings from the phase III CheckMate-238 trial."

Here's a synopsis of Opdivo's approvals by the FDA:  History of Opdivo from

Development History and FDA Approval Process for Opdivo

Sep 22, 2017Approval  Opdivo gets Approval for  Hepatocellular Carcinoma Previously Treated with Sorafenib
Aug  1, 2017Approval Opdivo approved in MSI-H or dMMR Metastatic Colorectal Cancer That Progressed after Treatment
Feb  2, 2017Approval Opdivo  approved in urothelial cancer Previously Treated then Locally Advanced or Metastatic 
Nov 10, 2016Approval Opdivo is the First Immuno therapy Approved in Head and Neck Cancer
May 17, 2016Approval Opdivo Approved for the Treatment of Hodgkin Lymphoma
Jan 23, 2016Approval Opdivo + Yervoy Approved in Unresectable or Metastatic Melanoma Across BRAF Status
Nov 23, 2015Approval Approves Opdivo to Treat Metastatic Renal Cell Carcinoma
Oct  9, 2015Approval Expands Approved Use of Opdivo (nivolumab) in Advanced Lung Cancer
Oct  1, 2015Approval Approval for Opdivo + Yervoy in BRAF V600 Wild-Type Melanoma
Mar  4, 2015Approval Expanded use of Opdivo to Treat Lung Cancer approved
Dec 22, 2014Approval Opdivo Approved for Advanced Melanoma
Dec  6, 2014Opdivo Demonstrates High Overall Response Rate of 87% for Treatment of Relapsed or Refractory Hodgkin Lymphoma
Nov 16, 2014Study Comparing Opdivo to Chemotherapy Demonstrates Survival Benefit
Oct 30, 2014Phase 2 Objective Response Rate and Survival Data for Opdivo in NSCLC to be Presented
Oct  6, 2014BMS Announces Collaboration to Evaluate Opdivo in Combination to Treat Non-Small Cell Lung Cancer
Sep 26, 2014Bristol-Myers Squibb Announces Multiple Regulatory Milestones for Opdivo 
Ratties are truly and for certain (along with at least one special mouse, my dear Edster!) amazing peeps.  And while one of us changes little alone.........together......The Rats of NIMH                                    (No Idiotic/Injurious/Insulting/Intensely awful Melanoma Here!!!)  HAVE CHANGED THE WORLD!!!!!Thanks and much love to each and every one of you.  Merry Christmas!!! - love, c 

Wednesday, December 20, 2017

Elderly melanoma patients and immunotherapy

A diagnosis of melanoma is devastating for anyone.  While effective treatment is what those of us with melanoma seek, it is understandable that considering therapy that is known to have the potential for significant side effects is concerning for all of us and likely even more so for elderly patients in need.  This earlier post helps diminish that concern:  With immunotherapy the elderly with melanoma may be down...but NOT out!!!  as the two patients in the case report tolerated immunotherapy with no greater difficulty than expected.  Now there's this:

Association of Immunotherapy With Overall Survival in Elderly Patients With Melanoma. Perier-Muzet, Gatt, Falandry, et al.  JAMA Dermatol. 2017 Dec 6.

Melanoma treatment has been revolutionized with the development of immune-based therapies that offer durable clinical responses in a subset of patients. Clinical outcomes after treatment by immunotherapy can be influenced by the host's immune system. The immune system is modified with age by age-related immune dysfunction.
To evaluate if age influences clinical outcome and immune adverse events in patients treated by immunotherapy for metastatic melanoma.

This was a single-center cohort analysis in patients treated with immunotherapy for metastatic melanoma between January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92 patients with metastatic melanoma treated with ipilimumab, nivolumab, or pembrolizumab were retrospectively analyzed.

Overall survival, progression-free survival, and immune-related adverse events were evaluated for each treatment line according to the patients' age.

A total of 92 patients were eligible and included in this study for a total of 120 lines of treatment. Fifty-four patients were included in the cohort that was 65 years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38 patients were included in the cohort that was older than 65 years (12 [34%] were female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at treatment initiation was 12.5 months. Patients older than 65 years treated with immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months) and overall survival (not reached vs 10.1 months) than younger patients in univariate analysis, and after adjusting on prognosis covariates. This was particularly true with patients treated with anti-programmed cell death protein 1. Common immune-related adverse effects were similar in both cohorts.

Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.

In this study of 92 patients treated with ipi, nivo, or pembro at a hospital in France, 38 of them were older than 65.  In that older subset, there was no increase in adverse events and progression free survival and overall survival data was even better than it was in younger patients.  This could be  a fluke (the better response rates in particular) given it is a review of only one set of 38 patients, but we already know that younger patients diagnosed with melanoma often experience more devastating results than older patients do.  Here is a post from 2014:  With melanoma: You can never be too rich or too thin! But, you can be too young!!!

Either way, sounds like good news to me.  Chipping away at melanoma...bit by bit!!  - c

For fun and celebration, check out this amazing still life from my hometown....and an artist who just happens to be close to my heart and a fab researcher for this blog: - photo of the day ~ Brainerd barber shop  Well done, B!!!! - les

Friday, December 15, 2017

Another look at a recent study of proteins in our blood that predict response to anti-PD-1!!!

A couple of days ago I posted this:  A simple blood draw to measure serum protein - predicts outcome for melanoma patients treated with anti-PD-1????

It is a review of the article you can find here and peruse yourself:  A Serum Protein Signature Associated with Outcome After Anti-PD1 Therapy in Metastatic Melanoma Jeffrey S. Weber, Mario Sznol, Ryan J. Sullivan, Shauna Blackmon, Genevieve Boland, Harriet M Kluger, Ruth Halaban, Antonella Bacchiocchi, Paolo A Ascierto, Marilena Capone, Carlos Oliveira, Krista Meyer, Julia Grigorieva, Senait G Asmellash, Joanna Roder and Heinrich Roder Cancer Immunol Res December 8 2017

Some of my peeps had a few more questions, and I found the whole shmegegge super interesting, (Especially when you think about it in light of all the other potential that a simple blood analysis has regarding tumor burden and other biomarkers:  Measuring cell-free DNA in melanoma patient's blood to determine tumor burden and prognosis!) so here is a more thoughtful analysis than my first.....

After a thorough review of the entire article, along with all the tables and figures with my trusty's what we got:

Dr. Weber made an earlier presentation of some of this data at a conference in it's been cooking a while.

The main gist is pretty straight forward: Researchers used pooled data from multiple institutions and several studies of ratties (n = 289) who took nivo, pembro, ipi, or the ipi/nivo combo (along with those of us who took nivo with peptide vaccines). Some of the ratties had already had ipi, before taking anti-PD-1 and some had not. Blood was drawn before the ratties started treatment. Those samples were analyzed using advanced techniques to tease out what proteins in the blood were present in the sensitive set (patients who responded) vs the resistant set (patients who did not). After that first examination was completed, researchers used the same protein markers on test sets. The protein markers were successful in distinguishing those likely to be sensitive (responders) from those who were likely to be resistant (non-responders). In addition, they analyzed the proteins to identify the mechanisms of sensitivity or resistance. There they found proteins associated with: 
1. wound healing
2. active phase reactants (the body's inflammatory response)
3. complement activation (another immune mechanism we use to respond to abnormal molecules – which could be anything from worms to cancer).

This test clearly worked to predict response for folks taking anti-PD-1 alone or taking ipi alone. However, when ipi/nivo was taken together the proteins were not predictive of response. (As an aside if you look at the graphs...Sets 2 and 3 are not currently significant, probably because the length of time passed at review of data was not adequate.)  You can take a look at the graphs in the link above or my pic below.

Researchers repeatedly note that application of this test to a larger group is needed to validate and further refine these results. Still – I am hopeful that knowledge of these proteins will provide guidance for future therapeutic interventions. For instance, if we could enhance wound healing while simultaneously decreasing inflammatory response and complement activation, we might be able to make anti-PD-1 therapy more effective. However, the current test as is - cause remember, these samples were taken BEFORE any of these ratties got any anti-PD-1 therapy - could refine prediction of who would benefit from current anti-PD-1 treatment and who may not.  For instance, if your blood samples showed proteins indicating that you were likely to respond to anti-PD-1 alone, especially if we were to examine that same blood draw for circulating tumor DNA and other biomarkers, it may help your decision making process when considering anti-PD-1 therapy vs the ipi/nivo combo with its increased rate of potential side effects.

Come on, researchers.  Let's get these tests out there!!!  Here's to the ratties! love, c

Thursday, December 14, 2017

Sew Chaotically! - The good, the bad, and the ugly!!! The ROBE to hell is paved with good intentions!!!

If I had one shred of pride, there is NO WAY I would share the following sewing disaster!!!  However, as my biologic children, along with all the others I care for daily will readily attest - "Pride???  She has none!"  I will sing, beg, dance, pantomime hygiene name it!  Whatever it takes to impress them with good health habits and foster their self esteem, I'll do!!  At this point in my life, I ain't got time for nothing but straight talk, whether it's about melanoma, health care as a right, the well being and education of our children, the importance of standing up for the least among us, or - sewing!  If I can share information that helps someone or makes them smile - I figure I did something worthwhile.  Now....don't get your hopes too high!!!!  I don't think I am going to change the world or teach anybody anything with THIS post!!!  But, here you go....

As you may recall, I made this jacket from a very lush fleece for a friend. Sew Chaotically! - Kimono Sashiko Jacket - Lisette B6464, plus 2 in fleece!  It went together beautifully.  It was awesome.  Everyone who saw it admired its cuteness, its finished seams, the symmetry of the collar!  And, hell! It was so easy...I made 2!!!!  Flushed with my own success, I thought - "I'll make everybody fleece robes for Christmas!!!  It will be fabulous and so easy!!!"

I even had a couple of patterns (more on that later).  This one seemed the best to use for my purposes, though it was decidedly ancient having been gifted to me from a sewist's stash years ago.  I confessed my plan to Rosie who was really psyched about the prospect!  Being cold natured she really WANTED a warm fluffy robe!  (I was pretty certain the other recipients would not be that excited about a robe...but I thought they could still enjoy one.) She happily joined me at our local JoAnn's to pick out the perfect fleece for herself and others.  With her love of purple she chose a lush purple plaid and a matching solid.

HOW DID IT GO SO WRONG????  I ask you.  Have you EVER seen a sadder excuse for a garment?  Of any sort?  Oh. My. LORD!!!!  I put forth a good deal of effort here!  EVERY seam was first stitched on my machine with the appropriate needle and walking foot...then meticulously serged.  Knowing Roo was probably the only person who truly wanted a robe, I didn't really want to make hers first, but she was my tiniest person and I reasoned I could better judge how to increase the size for the others by making hers first.  And, yes...I will address the elephant in the picture.  What the hell happened with those pockets?????  I actually worked hard on their placement!  I MEASURED carefully!  Basted in place.  Laying flat they are perfect.  Hold the robe up....and there you go!

Incredibly deflated, I tackled one for the Jamester!  Rosie had picked his material carefully.  Given the bunch of mess her robe with its contrasting "neck band" had turned into, I decided to skip that business!  To heck with using the walking foot first as well.  I just sewed the sucker up on the serger and folded the neck over.  Results are only mildly better generally.  Pocket placement was intentionally skewed with a slightly better outcome.  By now...I am beyond!!!  Why the hell had I thought this was a good idea????  How is this turning out so very, extremely badly?????!!!!  I texted Roo.  "Do you like perfect pie, symmetric and pristine, as though straight from the bakery?  Or do you find you prefer the rustic variety, with the tasty, albeit cracked and somewhat broken crust...delicious and baked with love?"  She replied, "Both?  Why?"  I said, "Never mind.  You and Jamie can have your durn robes.  They are horrifying.  I'll bring them to our workout.  My only requirement is that you have to open them together and I need pics!!!"

These pics...

...have made me (and many others)....


...until we had tears....

...and our stomachs hurt.  Is the Jamester a good sport or what?????

Sadly, it just gets worse!!!!  Here B is being forced to try out the robe for Fred-o who is a great deal taller, so I can try to gauge how to hem it!  However, at this point, I was getting a bit wiser....or no longer cared!  Note there is only one pocket!  (Those suckers can't look as jacked if you don't have one next door to compare it to!!!) And, I had adopted serged edges as a finished seam!!!
Wizard wand, anyone????

The fun and games that is this disaster, continued.  Here I'm trying to get my crazy model (I mean love of my life) to help me decide about sizing for a taller person with boobage!

As you might imagine ~ his 'help' was of a limited nature.

By this point, my model was about as cooperative as a recalcitrant, cranky toddler in need of a nap and a cookie.  "Hold up your arms so that I can see where to hem the sleeves," I order.
"I can't, they're tired."
"Oh, Bent.  Come on, you only held them straight for two seconds!!!"
I reply.
"This is making me really hot. It's fine. I think you're done."
(Cleaning up all the fleece fuzz that covered EVERYTHING...took hours!!!!)

Clearly, thus far, I have covered the bad and the ugly.  This last IS the good, and while it did serve to restore a bit of my sewing esteem, it seems rather wrong and selfish somehow.  To struggle on to the bitter end.... 
My sweet B gave me this (picture above) for my last birthday.  Initially, on opening the package under his watchful eyes, I was simply confused.  What the - ????  It says "women's robe".... "Purl Soho" .... in a clear package labeled ... "table cover"????  Wait a minute!  B had downloaded the Purl Soho robe pattern, remembering that I had admired it.  Then, and I think this is pretty ingenious, bought one of those thick paper table "cloths" on which to create the ensconced within the original plastic bag!!!   How sweet is that???  Perhaps I should have used this pattern all along, but he had drawn out only the small size (which would have worked for Rosie) but I wasn't certain it would work out very well with the thick fleece.

Anyhow, I made this rather lovely robe for.....ME!!!!!

The pattern is very simple with some ingenious little tricks including a hanging loop. Insides are finished with both French and flat felled seams.  The material is a super soft flannel B picked up and some remnants of a woven cotton I had left over from another project.  Both were very easy to work with.  Some folks complained of limited space in the underarm area.  I had no problems and just made the pattern as is.  However, there is a gusset piece that you can download as an addition, by Purl Soho, if you think it will be an issue for you.

I really love it!  Still, it seems super wrong to make crappy crap for others and something really nice for yourself!!!

Those smiles though!!!!!  They make my "robe to hell" totally worth it!!!  (Sorry Fred and Irina!!  I tried, I really did!!!!)
Merry Christmas, guys!!!!  Sew chaotically!  (As though I know any other way!!!) - ;>) les

Tuesday, December 12, 2017

A simple blood draw to measure serum protein - predicts outcome for melanoma patients treated with anti-PD-1????

So this is interesting:

A Serum Protein Signature Associated with Outcome After Anti-PD1 Therapy in Metastatic Melanoma. Sznol, Sullivan, Blackmon...Ascierto...Weber.  Cancer Immunol Res. 2017 Dec 5.

A mass spectrometry analysis was performed using serum from patients receiving checkpoint inhibitors to define baseline protein signatures associated with outcome in metastatic melanoma. Pre-treatment serum was obtained from a development set of 119 melanoma patients on a trial of nivolumab with or without a multi-peptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix assisted laser desorption/ionization time of flight mass spectrometry. These data combined with clinical data identified patients with better or worse outcomes. The test was applied to five independent patient cohorts treated with checkpoint inhibitors and its biology investigated using enrichment analyses. A signature consisting of 209 proteins or peptides was associated with progression-free and overall survival in a multivariate analysis. Test performance across validation cohorts was consistent with the development set results. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for 'sensitive' relative to 'resistant' patients. The test was associated with survival in a cohort of ipilimumab-treated patients. Test classification was associated with acute phase reactant, complement and wound healing pathways. We conclude that a pre-treatment signature of proteins, defined by mass spectrometry analysis and machine learning, predicted survival in patients receiving PD-1 blocking antibodies. This signature of proteins was associated with acute phase reactants and elements of wound healing and the complement cascade. This signature merits further study to determine if it identifies patients who would benefit from PD-1 blockade.

In line with my last post....researchers keep looking for a biomarker via a simple blood draw that will predict response to a particular treatment, indicate tumor burden, note disease progression or regression, etc.  Here, researchers looked at proteins in the blood of 119 "melanoma patients on a trial of nivo with or without multi-peptide vaccine and from patients [in other immunotherapy studies]". 

Hmmmm.....anybody know ratties who took nivo with peptide vaccines???????  C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!  Damn!!!  The places my blood has gone with nobody telling me NOTHING about it!!!!!!!!!!!!!!!!!

ANYWAY!!!!!  In this report, researchers found that a certain set of proteins, found in the blood of patients with melanoma BEFORE treatment, "predicted survival in patients receiving PD-1 blocking antibodies."

This could be very important for folks making a decision about what treatment is best for them.  Melanoma is not kind to those who waste time.  A way to know which treatment to spend your time taking could be life saving.

Wonder what THIS rattie's proteins showed?  Seriously, how is it that clinical trials use ratties and fail to  inform them of the results of their OWN tests?  How is this okay?  WHY wouldn't you let the folks who put their lives, dollars, families, blood, protein, EVERYTHING on the line - yes, for themselves...but also for the reputations (and CV's) of researchers and facilities as well as the monetary/stock value of Big Pharma - the results determined from their literal blood, sweat and tears?  Just asking!  Sadly....not expecting answers.  Can only hope that these results will benefit melanoma peeps in the future!!!  - c

Saturday, December 9, 2017

Measuring cell-free DNA in melanoma patient's blood to determine tumor burden and prognosis

I have spent years yelling about finding a reasonable marker through a simple blood draw to determine disease burden, response to therapy, and prognosis for melanoma patients.  Here's a zillion reports - Markers for melanoma- looking at utilizing everything from progression on scans, t-cell exhaustion, lymphocytes, circulating CD8 and CD4 t cells, eosinophils, LDH, melanoma antigens, to circulating tumor cells to determine the status of a melanoma patient's disease burden.

On the topic of circulating tumor DNA alone there are these:  Circulating tumor DNA in melanoma
It can be used to determine level of disease, progression, BRAF status and response to treatment.
Now there's this:

Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients. Valpione, Gremel, Mundra, et al.  Eur J Cancer. 2017 Nov 23.

Tumour burden is a prognostic biomarker in metastatic melanoma. However, tumour burden is difficult to measure and there are currently no reliable surrogate biomarkers to easily and reliably determine it. The aim of this study was to assess the potential of plasma total cell free DNA as biomarker of tumour burden and prognosis in metastatic melanoma patients.

A prospective biomarker cohort study for total plasma circulating cell-free DNA (cfDNA) concentration was performed in 43 metastatic melanoma patients. For 38 patients, paired blood collections and scan assessments were available before treatment and at first response evaluation. Tumour burden was calculated as the sum of volumes from three-dimensional radiological measurements of all metastatic lesions in individual patients.

Baseline cfDNA concentration correlated with pre-treatment tumour burden. Baseline cfDNA levels correlated significantly with hazard of death and overall survival, and a cut off value of 89 pg/μl identified two distinct prognostic groups. Patients with cfDNA greater than/= to 89 pg/μl had shorter OS (10.0 versus 22.7 months) and the significance was maintained when compared with lactic dehydrogenase (LDH) in a multivariate analysis. We also found a correlation between the changes of cfDNA and treatment-related changes in tumour burden. In addition, the ratio between baseline cfDNA and tumour burden was prognostic.

We have demonstrated that cfDNA is a surrogate marker of tumour burden in metastatic melanoma patients, and that it is prognostic for overall survival.

These tests work!  It is time to make them a reality for those with melanoma! - c

Thursday, December 7, 2017

Pembro for mucosal melanoma vs response rate to nivo alone vs the ipi/nivo combo

A diagnosis of melanoma is bad enough.  Unfortunately, folks with mucosal melanoma have an even more difficult time.  Here's a review of two articles:

This report (Jan 2017):  Evaluation of response to nivo or ipi/nivo in Cutaneous and Mucosal Melanoma  Notes ~  889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months and 6.2 months for mucosal and cutaneous melanoma, with objective response rates of 23.3% and 40.9%, respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months and 11.7 months for mucosal and cutaneous melanoma, with objective response rates of 37.1% and 60.4%, respectively. 

Efficacy of pembrolizumab (pembro) in patients (pts) with advanced mucosal melanoma (mucMEL): data from KEYNOTE-001, 002, and 006. Hamid, Ribas, Hodi, et al.  Society for Melanoma Research 2016 Congress.  Published 29 January 2017. 

Pembro has demonstrated efficacy and a manageable safety profile in advanced MEL. We assessed outcomes of pts with advanced mucMEL enrolled in KEYNOTE-001 (NCT01295827), KEYNOTE-002 (NCT01704287), and KEYNOTE-006 (NCT01866319). Pts received pembro 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W. Response was assessed per RECIST v1.1 by independent central review. Of the 1567 pts in the pembro arms who received greater than/= to 1 pembro dose, 84 (5%) had mucMEL. 57% of pembro-treated pts with mucMEL were women, 49% were aged greater than/= to 65 y, 32% had ECOG PS 1, 48% had elevated LDH, 8% had BRAFV600 mutant tumors, 81% had M1c disease, 58% had baseline tumor size greater than/= to 77.7 mm (ie, median in total population), and 70% with known PD-L1 status had PD-L1–positive tumors. 90% of pts received greater than/= to1 prior therapy: 37% received 1, 45% received 2, and 8% received greater than/= to 3; 39% received prior ipilimumab (ipi). In pts with mucMEL, ORR was 19%, DCR was 31%, median PFS was 2.8 months, and median OS was 11.3 months. In the 16 responders, median time to response was 12.4 weeks (range, 11.1–84.1), 12 (75%) were alive without subsequent progression, and median response duration was 27.6 months (range 1.1+ to 27.6). In ipi pretreated pts with mucMEL, ORR was 15%, DCR was 27%, 4 of 5 (80%) responders were alive and without subsequent progression, and median response duration was 27.6 months. In the 1483 pembro-treated pts with non-mucMEL, ORR was 33%, DCR was 47%, median time to response was 12.4 weeks (range 3.7–144.0), 72% of responders were alive and progression free, median response duration was NR (range 1.3+ to 38.8+), median PFS was 4.2 months, and median OS was 23.5 months. Pembro is active in advanced mucMEL and provides durable activity regardless of prior ipi.

So...according to these studies:  Folks with mucosal melanoma who were given nivo alone had an objective response rate of 23% (cutaneous melanoma = 40%).  Those with mucosal melanoma given the ipi/nivo combo had a 37% objective response rate (cutaneous = 60%).  With pembro,  folks with mucosal mel not previously treated with ipi the ORR was 19%.  Those with prior ipi had a response rate of 15% to pembro.  (Generally the ORR of patients with cutaneous mel treated with pembro was 33%.)

In the end, folks with cutaneous melanoma can respond to nivo (Opdivo) or pembro (Keytruda) alone (and those responses can be durable).  However, it seems the response rate to the ipi/nivo combo is much better...though none of the response rates are as high as those that can be attained for cutaneous melanoma patients.  Hang in there, ratties.  Wishing you all my best. - c

Monday, December 4, 2017

Sew Chaotically! - Exercise tops for Roo - M7610

Or....waste not want not!  Or...playtime!!  Or...tops that are a party in the back!!! - could all serve as appropriate titles for this post.  As I've mentioned, Rosie and I are getting fit (read - having our booties kicked!!!) in a weekly Barre Boot-camp exercise class.   Rosie has always been a hardcore runner, spoiling me with workout/running/hiking tops as gifts, but pretty much just going with a jog bra and tank/tee for her own workouts.  With our new gig being downtown and all...I thought it would be fun to make her a couple of things.  And what with having recently made some knit tops...there were odd bits and bobs of left overs lying about!!!

I picked up this pattern when it was on sale and thought it would give me some perfect options.
I had this bit of underwhelming grey stretch knit, previously used as a dress lining, at hand.
However, it seemed the perfect foil for my last bit of Pinky Pink Power Woman  fabric!  Sure enough, at our last class, the combo cast its spell!  As Roo powered through her workout, a fellow classmate said, "Rose, I love your top!  It's so cute.  Where did you get it?"  Are those not the perfect words to warm a sewist's heart????
With this remnant of the super soft knit I used in my Basic InstincT Tee....
...I made this!!  The pattern has you make a twist...but that turns out rather wonky.  I tried a double twist...and a knot.  In the end, I settled on a folded gather, stitched in place.  Both are a size 12.  I folded under a hem on the neck, arms, and bottom, but left a simple serged edge as the finish for the grey pieces front and back necklines.  My only adjustment was to scoop out the neck on both tops just a bit.  When I make them again, Rosie requests that they be a tad longer.
These were fun easy makes!  Now "sit down in your favorite chair" my real live Pinky Pink Power Woman!!! - love, mommy

Saturday, December 2, 2017

T-VEC plus ipi vs ipi alone ~ along with additional T-VEC data...

I've been posting updates about T-VEC since 2015.  Put 'T-VEC' in the search bubble and you will find a zillion articles.  Here's one from ASCO of this year, covering intralesional/intratumoral therapies generally and T-VEC in particular:  ASCO 2017: All things intralesional/intratumoral

Now there's this:

Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. Chesney, Ppuzanov, Collichio...Hamid...Lebe...Andtbacka, Kaufman.  J Clin Oncol. 2017 Oct 5.

We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. 

Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, less than/= to 4 mL × 106 plaque-forming units/mL; after 3 weeks, less than/= to 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. 

One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone( n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response. Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade greater than/= to 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Patients with the ipi/T-VEC arm certainly did better than ipi alone.  In this post: The Future for Melanoma Treatment = Combo's! Dr. Weber breaks it down -  From the interview the post covers, Dr. Weber notes:

Checkpoint Inhibition Plus Talimogene Laherparepvec
The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.8 “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.9 This regimen is now in phase III trials.

To that last point...combining T-VEC with anti-PD-1 may be even better than combining it with ipi with far fewer side effects:  T-VEC (Talimogene laherparepvec, Imlygic...whatever you want to call it) - oncolytic virotherapy may improve the efficacy of anti-PD-1 by changing the tumor microenvironment!!

One more personal report I can share ~ If you read the first report carefully, you will see that among side effects, researchers note  "chills (combination, 53%; ipilimumab alone, 3%)".  Clearly, if "chills" occur at a rate of 53% with T-VEC plus ipi and only at 3% with ipi alone...the "chills" are due to T-VEC!!!  A dear one of mine is currently taking pembro ( anti-PD-1 product) with T-VEC and tells me that he has been dealing with significant fevers.  Which of course would be the case, if a researcher reports "chills"!!!  Isn't it interesting how folks who are NOT experiencing the side effects report them??????

Thanks for sharing and being an awesome rattie, Mark!!!  Hang tough, the rest of you ratties out there!!! - c