Signs of spring....

For all my more northern peeps....Jonathan, Steven, Eric, Lucy and Sue, John, Allyson, Cat...for all of you who may need a sign that spring really is on her way....

Have a beautiful week.  love, c

Blood markers associated with clinical outcome of melanoma treated with ipi

Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab.  Martens, Wistuba-Hamprecht, Geukes Foppen, et al. Clin Cancer Res. 2016 Jan 19.

[This study was done as an attempt to] identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Frequencies of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan-Meier- and Cox-regression-analysis including calibration and discrimination by C-statistics. Low baseline LDH, absolute monocyte counts (AMC), Lin-CD14+HLA-DR-/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. 43.5% of patients presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2-0) was also associated with OS in the main study and additionally in an independent validation cohort. A baseline signature of low LDH, AMC and MDSCs as well as high AEC, Tregs and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g. PD-1 antibodies, is warranted. So...common themes we have been seeing lately:  LOW LDH, AMC and MDSC's bode well for those treated with immunotherapy.  More related info here: LDH: LDH as predictor of outcome Being female with low LDH and no ulceration...good with BRAFi White cells: Neutrophils as prognostic predictor MDSC's: Markers for response to immunotherapy T-regs: How to make anti-PD1 work better Have a beautiful weekend! -c

Sew Chaotically! - Ripped jeggings? Darn and decorate!

What to do when your daughter rips the right knee in her favorite PURPLE jeggings???

Darn and decorate!  Van Gogh's got nothing on me!

 Hee hee!  I thought they turned out pretty well!!!  Love my Roo! - c

Time to Response...Ipi vs Nivo and ipi

Sometimes a picture is worth a thousand words. This slide is from a paper comparing the nivo/ipi combo vs ipi alone by Hodi et al. 2015.  Median time to response for both is roughly three months (or approximately 10-12 weeks).  Duration of response in these patient is not yet reached.  Roughly 80% of those responding have an ongoing response in both groups.  68% of those who had to discontinue the combo had a complete or partial response.....a very good thing!!!  There are documented outliers who responded at anywhere from 6 to 10 months....just say'n!  Of course we have to remember that the percentage of responders for the combo is about 50-60% vs only 10-15% for ipi alone.

For what it's worth.  Celeste

Damn Spam Blocker...For Chris, et al...and all the rest of you newly diagnosed with melanoma!!!

Tried to post this on one of the melanoma forums...but length and links seem to trigger their spam blocker...so here you go:

Dear Chris (and the rest of you on this thread),

I usually refrain from comment on folks in the early stages of melanoma. I am not the poster child you would like to see in the mirror...in some ways...and Janner (a frequent and excellent contributor to this forum) is more of an expert in this regard than I am.  However, this discussion made me feel that there may be some things I can say that you need to hear.  And, just so you know....there are strange folks in the world who will pose as a variety of things (patients included) who will try to convince a desperate group of people to utilize their "product".  Some of us have been in this game a long time...which is good!!!....and we have seen this happen and try to stand guard for others if we feel that may be what is going on....though I don't believe it was in this case.

So...who the heck am I anyway?  I am Celeste (Bubbles).  I was diagnosed with my first melanoma primary cutaneous lesion in 2003.  It was only 0.61mm in depth with no ulceration.  Even so I had a positive sentinel node and underwent a complete lymphadenectomy of right axilla which showed no other positive nodes.  I had no additional treatment...mostly because there was none available except interferon....which comes with side effects that, for most, are far worse than those anti-PD1 products now produce despite absolutely no evidence that it improves survival.  Almost 5 years later in 2007..I developed a second primary on my forearm....had it (only 0.5mm) and the sentinel node removed with another complete L ax lymphadenectomy.  None of those nodes were positive.  Still no drugs other than IL2 and interferon available.  I watched and waited.  On a routine scan in 2010, followed by bronchoscopy to identify the blob, melanoma was found in my lung.  An MRI of my brain showed a met there as well. Surgery to remove the blob and the right upper lobe of my lung.  SRS (radiation) to the brain met.  This was just 2010, y'all!!!!  Guess what?  STILL...not a single other melanoma med with FDA approval.  I participated in a 2 1/2 year, NED arm, of a Nivo/Opdivo trial that started in late 2010 and remain NED ever since.

Now...you see how I am not the girl you want to be when you grow up?  The truth is....most of you will NOT be me.  That's the good news.  You should be vigilant, watch your skin, live your life.  The other truth is...you should live your life no matter what, but I digress...

I don't know a great deal about Decision DX.  I don't think it is a bad thing...but I don't think it is going to give you a great deal of information either way.  As long as you take your "result" with a grain of salt....I don't think you have anything to lose.  What you do need to keep in mind....at least at this time....is that the only "data" that is available about it is being put out by the company that makes/sells it:  Castle Bioscience.  That doesn't make it bad...just something to think about.

Here's what I would most certainly be thinking about if I were in your shoes!!  And remember....I HAVE BEEN!!!!  PCR testing for circulating melanoma cells...or bits of them.  Sadly, these are not completely validated or available at this moment.  But, if these get going the way I think they will,  we will be able to glean REAL info about what is in our bodies.  The implications are huge!  If we really knew what was floating around in there...we could decide if we need systemic treatment or not and whether we are responding to a certain treatment...or not!!!
Here are some posts you might find helpful:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2015/12/circulating-tumor-cellshow-they-may.html

http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2015/12/pcr-testing-for-circulating-melanoma.html

The other difficult issue is whether or not to do sentinel node testing...and if that is positive....whether to do a complete dissection of the nodes in that area.  As you can see above, I chose to do it.  But it is not completely clear whether that really affects outcome or not.  Here is a post I just put up today that contains a link to another recent study within it:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2016/02/patients-wtih-microscopically.html

In addition to the fact that your prognosis is pretty good....should you have a recurrence or advancing disease tomorrow or years down the road....you have options.  BRAF inhibitors, if your tumor is BRAF positive.  Testing for which you should probably have done on your tumor samples now.  Ipilimumab, a type of immunotherapy...only a 15% or so response rate...with a fair risk of side effects...but has been a life saver for many.  Anti-PD1 products (Nivolumab/Opdivo and Pembrolizumab/Keytruda) with about a 40% response rate and far fewer side effects than ipi.  Additionally....ALL these products are currently in trials with Stage III and IV patients who are NED...as adjuvant treatments.  I was a rattie in one of these early NED trials myself and most of my fellow ratties and I have done far better than expected.

So lots that is scary...lots to learn.  There are many here to help you....including my dear Ed.  Melanoma makes folks testy.  Wishing each of you my best, Celeste

"Patients with microscopically negative/PCR+ SLN have increased risk for nodal recurrence that was mitigated by CLND"!

Molecular Staging of Sentinel Lymph Nodes Identifies Melanoma Patients at Increased Risk of Nodal Recurrence.  Kimbrough, Egger, McMasters, et al. J Am Coll Surg. 2016 Jan 14.

Molecular staging of sentinel lymph nodes (SLNs) may identify patients who are node-negative by standard microscopic staging but are at increased risk for regional nodal recurrence; such patients may benefit from completion lymph node dissection (CLND).

In a multicenter, randomized clinical trial, patients with tumor-negative SLNs by standard pathology (hematoxylin and eosin [H and E] serial sections and immunohistochemistry [IHC]) underwent reverse transcriptase polymerase chain reaction (PCR) analysis of SLNs for melanoma-specific mRNA. Microscopically negative/PCR+ patients were randomized to observation, CLND, or CLND with high-dose interferon (HDI). For this post-hoc analysis, clinicopathologic features and survival outcomes, including overall survival (OS) and disease-free survival (DFS), were compared between PCR+ patients who underwent CLND vs observation. Microscopic and molecular node-negative (PCR-) patients were included for comparison.

A total of 556 patients were PCR+: 180 underwent observation, and 376 underwent CLND. An additional 908 PCR- patients were observed. Median follow-up was 72 months. Disease-free survival (DFS) was significantly better for PCR+ patients who underwent CLND compared with observation. No statistically significant differences in OS or distant disease-free survival (DDFS) were seen. Regional lymph node recurrence-free survival (LNRFS) was improved in PCR+ patients with CLND compared to observation. The PCR+ patients in the observation group had the worst DFS; those with CLND had similar DFS to that in the PCR- group. 

Patients with microscopically negative/PCR+ SLN have an increased risk of nodal recurrence that was mitigated by CLND. Although CLND did not affect OS, these data suggest that molecular detection of melanoma-specific mRNA in the SLN predicts a greater risk of nodal recurrence and deserves further study.

Hmmm....as ever....in melanoma, decisions are not simple - especially when this study is juxtaposed against the recent release of the Sunbelt Melanoma Trial final report: Sunbelt Melanoma trial final results  I still have to believe that getting that S#!T out of there has got to be a good thing!  But, messing with lymph nodes can be a painful, miserable proposition with the significant risk of lymphedema.  So....could robots do that job better?

Robotic-Assisted Transperitoneal Pelvic Lymphadenectomy for Metastatic Melanoma: Early Outcomes Compared with Open Pelvic Lymphadenectomy.  Dossett, Castner, Pow-Sang, Sondak, et al.  J Am Coll Surg. 2016 Jan 14.

In the absence of iliac or obturator nodal involvement, the role of pelvic lymphadenectomy (PLND) for melanoma is controversial, but for select patients, long-term survival can be achieved with the combination of superficial inguinal (inguinofemoral) and PLND. Open PLND (oPLND) is often limited in visual exposure and can be associated with considerable postoperative pain. Robotic PLND (rPLND) is a minimally invasive technique that provides excellent visualization of the iliac and obturator nodes. Outcomes comparing the open and robotic techniques have not been reported previously for patients with melanoma.

We reviewed our experience with rPLND for melanoma and compared clinical and pathologic results with oPLND. We evaluated operative times, nodal yield, and short-term oncologic outcomes.

Thirteen rPLND (2013 to 2015) (15 attempted, 87% success rate) and 25 oPLND (2010 to 2015) consecutive cases were completed. Pelvic lymphadenectomy was combined with an open inguinofemoral dissection in 8 of 13 (62%) robotic and 17 of 25 (68%) open cases. Median length of stay was shorter in the rPLND group, with 1.0 vs 3.5 days for pelvic-only cases and 2.5 vs 4.0 days for combined ilioinguinal cases. Median operative time (227 vs 230 minutes;) and nodal yield (11 vs 10 nodes) were not different between rPLND and oPLND.

Robotic PLND offers a safe, effective, minimally invasive approach to resect the pelvic lymph nodes in patients with melanoma, with no significant difference in nodal yield or operative times, but a shorter length of stay compared with oPLND.

Well, hmmmmm....again.  No impressive increase in the number nodes removed nor significant decrease in time on the operating table...but a decrease in length of hospital stay.  Perhaps over time we will find that that will contribute to the development of fewer side effects like nerve damage and lymphedema.  Have to wait to see what the ratties tell us.

Hang in there - c

Sew Chaotically! - Knits/Serger Learning curve!

A forced snow day (Yes, in TN we have snow...at times...and yes...many of us actually know how to drive in it!! However, it is almost always accompanied by an underlying layer of ice!!) and the plan to make this....

...gave me the time and determination to try to better understand the way to work with knits which spiraled into learning about my serger and the walking foot and....   After a two day marathon of reading articles, blogs, watching tutorials, and practice...my brain is full!!!  But here are some of the best sites, info and techniques I found!! First pearl:  Use serger with thread tree completely elevated!  Keeps threads from getting messed up and breaking!  Who knew????  (Not me, til now!)

From: sergerpepper - The Ultimate SergerDictionary

From: sergerpepper - 10 best beginner's serger tips

I thought this video was particularly good.  Pearl:  The lower looper thread must go OVER the upper looper!!!!  From: Make It Handmade - Threading your serger

I feel so much better now!  Actually, started blank and threaded the whole she bang!!!  But, here's another:  From: So sew easy - How to thread the Brother 1034D serger

Regarding tension!  The whole topic of sewing machine tension makes me TENSE!!!! This tutorial really helps.  Pearls for serger tension: The higher the number = the tighter the thread.  The needle tension is too tight if the fabric puckers.  The needle tension is too loose if there are loops of thread on the back of the fabric. Setting at #4 is usually a good place for all fabrics and sewing on the serger. From: Make It Handmade - Perfecting Serger Tension

From: Make It Homemade - Understanding Serger Features

From: Make It Homeade - How to thread your serger out of order

From: Make It Handmade - How to Serge Curves

From: sergerpepper - The 30 Best Tips for Sewing Knits

I've done some sewing with knits, but didn't feel like I knew what I was doing!!!  I'm feeling better after this!  Pearls:  Cut your pattern pieces so that the stretch runs ACROSS the body...not up and down long ways!  On the other hand, for neck and sleeve bands...the stretch should run the length of the band.  Both make sense...but it really helps to spell it out!!!  Luckily, having already cut out the knit dress above for Roo.....I did it right!!!  From: Lladybird - Conquering Knits

I knew this had to be a good plan once I saw this tutorial!!!  B is the bomb and got me some STRETCH stay tape. (Not so easy to attain and very different from your basic "stay tape" as the 'stretch' is definitely needed when working with knits!!!)  So, as practice I re-hemmed a t-shirt dress that was still a bit long after I had hemmed it by hand once... 

You can't see the stitches....but you can see it IS lumpy!

...and the way the hem was so even and flat with the stay tape and double needle stitching...

I could have used black thread in the serger, when I went round the hem after I cut it off, before hemming.  But, despite my new found serger threading prowess....wasn't worth it!!!!

...is nothing short of a miracle!!!  From: so-sew-easy - How and where to use knit stay tape

A little learning curve on how to thread my machine...after that....easy peasy!  From: So-sew-easy - How to use a twin needle

From: Sewing Parts Online - How to use a walking foot

From: The Seasoned Homemaker - The walking foot

And generally - Colette Patterns Blog has lots of amazing tutorials that are free!  I did actually purchase The Colette guide to Sewing Knits and it was totally worth it!

Hope this helps some of you learn great tips for using your serger or sewing knits!  Now on to sewing Roo's dress and a whole bunch of other knits just BEAUTIFULLY!!!  Hee, hee! - c

Good News! Melanoma Patients who failed ipi had response rate of 30% to Nivo with no increased rate of side effects!!!

This data comes from an arm added to the Nivo/Opdivo trial I participated in.  When making my decision, in 2010, to participate or not, the two arms were - nivo with vaccines in NED Stage IV patients vs active/advanced disease Stage IV patients.  At that time, talk was that ipi would finally be FDA approved in spring of 2011 (It was approved for patients with advanced disease that March.) and it was anticipated that if you took ipi first, the FDA and the powers that 'WERE', would not ALLOW you to take anti-PD1 later as the accumulation of side effects, etc. would be too much! THEN, the powers that 'were' declared that NO WAY were side effects from immunotherapy cumulative...BUT, if you had had a bad experience due to side effects on ipi, NO WAY could you take anti-PD1.  Then, they made failing ipi a pre-req for taking anti-PD1!!!  Oh, my!  Well, today we KNOW that while on immunotherapy....side effects can indeed be cumulative (increasing and worsening over time) but now.....we also know this:

Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab.  Weber, Gibney, Kudchadkar, et al. Cancer Immunol Res. 2016 Feb 12.

"The checkpoint inhibitor nivolumab is active in metastatic melanoma patients who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Response rate for ipilimumab-refractory patients was 30%. Median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when followed up a median of 16 months. One and two year survivals were 68.4% and 31.2%, respectively. Ipilimumab-naïve and -refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids, tolerated nivolumab well, with 62%  having complete or partial remissions or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSCs) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab."

So....folks who had problems with side effects when taking ipi could still be managed well when placed on nivo.  And....patients in this study whose tumors had failed to respond to ipi, still gained a 30% response rate to nivo. (Here's a link to more data related to ipi/nivo sequential dosing: Sequential nivo then ipi - ORR of 41%. Ipi followed by nivo - ORR of 20% ) 

I think the connection between increased levels of MDSCs and poor outcomes is something that deserves additional research.  Here's a link to a post that speaks to what they are, what they do, and what could possibly be done to improve response rates in spite of the little suckers: Markers for response to immunotherapy

We've come a long way, ratties!!!  You are awesome!!! - c

Sew Chaotically! - Coat 2 - Very Easy Vogue 9136

Collar options!!!

This coat went together very easily.  I made version A, but with inserted side pockets rather than the patch ones.  I used the same fabric, a soft, 100% washable cotton, that I used with this plaid skirt.
It is thick, but drapes pretty well.  The pattern called for interfacing to be used in the collar, front pieces and back belt.  I did so in the belt, but it was pretty stiff and heavy so I passed on using it in the other pieces and I am glad I did.  The sleeves were put in flat...per sewing instructions...and it worked like a charm. My only crisis was the belt...which, when made to size per pattern instructions was WAY too big for me.  I didn't mind the looseness, but the weight of it and bulk in the back of the coat, made the front hang weird.  Now...if I had had sense and foresight....I would have made the belt fit at the start.  It is one of the first things you do...making it and attaching to the back at the side, long before sleeves and side seams happen....which is cool since it is then neatly attached within your coat.  However, I was basically done when I figured out the issue.  I could have taken out the side seams.  But...being slightly lazy and extremely fearful that doing so would ruin the soft, slightly fluffy fabric, I ended up taking up the center of the belt to the appropriate size (by 4.5 inches to be exact!!!), and then using buttons to cover my "mess-up" and as a way to actually tack the belt in proper position to the back of the coat.  So...there you have it!!  Winter coats...DONE!  I may make a fuzzy purple one for Rosie next year per her request and it should be easy knowing what I know now!!  Interestingly, after having finished my blanket coat and looking about the internet for tips on making this one (There really weren't any...so here you go, peeps!!) I did find this:  If you've never sewn a coat before start with one of these patterns!  

I think the red coat is prettier in some ways. But, I am proud of this one too, and it has the benefit of being warm, cozy/casual (Though you could dress it up with a dark pencil skirt and heels!!), and easily tossed in the washer and dryer!  Stay warm! - c

Intestinal bacteria as a way to determine risk for ipi induced colitis!

I've previously talked about how certain cooties in our gut can serve us well in all sorts of ways.  There was even a study noted in this link: Cooties in our gut keep us skinny, smart, and cure cancer? that found Bifidobacterium could promote antitumor immunity and facilitate anti-PD-L1 efficacy!  Now there is this: 

Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.  Dubin, Callahan, Ren, Wolchok, et al.  Nat Commun. 2016 Feb 2.

The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy.

It would certainly be helpful to have a head's up about who is more at risk for the development of colitis when treated with immunotherapy!  Perhaps other options would serve the patient better or if immunotherapy is undertaken anyway, a prior warning could promote a more watchful eye and aggressive, prompt treatment should any adverse symptoms appear.  Best - c