Sunday, August 19, 2018

SLNB and melanoma patients!! Again!

The topics of sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) have been more than covered here!!  But, melanoma is a scary world to say the least, and folks are most frightened right at the time they are having to make these decisions! So, there was this:

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

And this:

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

Now there's this:

Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations. Verver, van Klaveren, van Akkooi, et al. Eur J Cancer. 2018 Apr 13.

In light of the evolving landscape of adjuvant therapy in melanoma and the recently confirmed absent survival benefit of completion lymph node dissection (CLND), it becomes important to explore possible consequences of omitting CLND, and whether it is possible to adequately stratify positive sentinel node (SN) patients solely based on information retrieved from the melanoma up to the sentinel lymph node biopsy (SLNB).

A retrospective cohort from nine European Organization for Research and Treatment of Cancer Melanoma Group centres was used. Patients were staged based on SLNB and CLND result according to the American Joint Committee on Cancer (AJCC) criteria and stratified by ulceration and SN tumour burden. These were incorporated in Cox regression models. Predictive ability was assessed using Harrell's concordance index (c-index) and the Akaike information criterion (AIC).

In total, 1015 patients were eligible. CLND led to upstaging in N-category in 19% and in AJCC stage in 5-6%. The model incorporating only ulceration and SN tumour burden performed equally well as the model incorporating substages after CLND. The model incorporating substages based on SLNB had the lowest predictive ability. Stratifying by ulceration and SN tumour burden resulted in four positive SN groups from which low-, intermediate- and high-risk prognostic classes could be derived.

Adequate stratification of positive SN patients was possible based on ulceration and SN tumour burden category. The identification of low-, intermediate- and high-risk patients could guide adjuvant therapy in clinical practice. Omitting CLND seems to have little consequences.  

This report simply reiterates what prior studies have shown.  SLNB is important for staging.  And looking at what the sentinel node shows as far as tumor burden, esp when you consider whether or not the initial lesion was ulcerated,  can be very helpful in evaluating risk and decision making regarding adjuvant treatment.  CLND did not really impact results.

Good luck, ratties!  You can do this! - c

Friday, August 17, 2018

Live chaotically! - REFASHION! (It covers a lot!)

"REFASHION!!!"  It's become a thing! A verb AND a noun!  Who knew?  But, hold up!!  Is this new (or news)????  NOPE!  Those of us who didn't have the where-with-all to attain the latest style learned years ago how to change that old prom/bride maid's dress into something we could wear on a date, sewed on that grosgrain ribbon to make like a prep-ster, and appropriated "men's wear" straight out of our man's closet.  Scarlet wasn't even the first refashioner when she yanked down those curtains and grabbed the tail feathers out of a rooster to create an amazing gown and a fascinator with southern charm!!!  Despite the cutting edge the latest "refashioners" like to think they're on, I love the idea and have lived it for years!!!  I hate waste and have often lacked the resources to purchase my ideals in sewing, cooking, gardening, home decor - you name it!  Plus, I love the creative nature of the process.  How do you turn trash into treasure?  Bunch of broken crayon nubs?  Make a candle! Empty wine bottle?  Nope!  That one is a beautiful carafe for vinegar.  The other one is a lovely vase.  Kid outgrows their favorite t-shirt?  Make them a pillow!  Got scraps?  Braid them into a rug.  Make them into a pot holder.  Sew up a warm throw for a bunch of freezing runners at those late night meets.  Veggies a bit too limp to stand up in a salad?  Girl, you got the makin's for soup!  Turn those potato peels into new flowers and veggies by composting!  The nifty cloth packaging from the same material purchased sheets and pillowcases often come in these days make lovely matching throw pillows with just a bit of "refashioning"!!!  So, despite my surprise at the smugness of this latest "refashionista" craze....I've got a few "refashion" stories of my own to share!!! 

What to do when your office of 13 years believes in team building through lots and lots and lots of t-shirts????  Well, there's a throw...that turned out larger than anticipated....

And tees revamped into racer-back work out tops...

...with one from a river rescue clean up for Roo!
Previously there was the little Polly top made out of a floral scarf and a fabric scrap...

When 'refashion' is used to refer to changing ready made garments into a more usable/beautiful piece in the eyes of its new owner, there is no one better than Sarah Tyau!!!  Check out her insta!!!!!

Seriously!  These renovations are nothing short of amazing!! 
B has gotten into the refashion craze as well...

...bending an overgrown crepe myrtle to his will!!!
A refashion of our yard, that added several "new" flower beds and plantings this spring and summer led to this:

This pepper plant has been crazy productive!!!
For all of that, sometimes a 'refashion' is even more personal.  After 13 years in my office where, by the grace of ever so many amazing parents, I was given the incredible blessing and privilege of caring for their precious children, the time has come for a change.  It has been one of the best and most gratifying experiences of my life.  But, as the office manager put it....

"Many moons ago, a Nurse Practitioner came to Peds Care hoping to find a practice where she could give great patient care to the children of this community...and she did just that and then some!!!!!  However, just as everything in life, this chapter is closing so new chapters can be written.

A quote from Lao Tzu says, "When I let go of what I am, I become what I might be."  I think this describes Celeste in its entirety!  She is letting go of what she has been for a very long time and venturing out to see what she might be for the next phase in her life.

Celeste, we bid you farewell but wish you the best in all your future adventures...and we know you will have many!!  LOL!!"

My heart is full.  I treasure the moments I have spent with every baby, toddler and teen. Every giggle and every tear will stay with me always.  I will forever wish my best to all the moms and dads I have had the privilege to help in our most important job ~ caring for our critters. 

Yes.  My heart is full.  But, the thing I've learned about hearts is that they can always grow to hold more.  Let's see what I can 'refashion' out of me!!!  Much love to all my dear PC peeps.  ~ love, c

Wednesday, August 15, 2018

Research that makes you scratch your head - brain power to kill cancer and sleep disordered breathing, relative to melanoma outcomes??? Ummmm, okay.

I don't know how to introduce these reports any better than as "head scratchers"!!!  Here we go!

Modulation of anti-tumor immunity by the brain's reward system.  Ben-Shaanan, Schiller, Azulay, et al.  Nat Commun. 2018 Jul 13.

Regulating immunity is a leading target for cancer therapy. Here, we show that the anti-tumor immune response can be modulated by the brain's reward system, a key circuitry in emotional processes. Activation of the reward system in tumor-bearing mice (Lewis lung carcinoma (LLC) and B16 melanoma) using chemogenetics (DREADDs), resulted in reduced tumor weight. This effect was mediated via the sympathetic nervous system (SNS), manifested by an attenuated noradrenergic input to a major immunological site, the bone marrow. Myeloid derived suppressor cells (MDSCs), which develop in the bone marrow, became less immunosuppressive following reward system activation. By depleting or adoptively transferring the MDSCs, we demonstrated that these cells are both necessary and sufficient to mediate reward system effects on tumor growth. Given the central role of the reward system in positive emotions, these findings introduce a physiological mechanism whereby the patient's psychological state can impact anti-tumor immunity and cancer progression.

Hmm... Okay...
1.  We have known for years that fewer MDSC's is a positive sign when dealing with melanoma.  Here's a bunch of posts and data on myeloid derived suppressor cells (MDSCs) and their role in melanoma In fact, I noted this in 2014 in regard to outcomes in my trial:

"MDSC  (myeloid derived suppressor cells)
"There was a trend towards lower baseline MDSC levels in non-relapsing patients compared to relapsing patients."  This bit of stuff and such along with other Treg/Tcell data comes your way thanks to us ratties sitting through leukapheresis twice during the trial. However, this is a bit I'm pretty psyched about.  There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients."

2.  In the entire article, linked here if you choose to read it ~  Modulation..., the authors note: 
"Epidemiological evidence supports a connection between the patient’s mental state and cancer survival, Nevertheless, many of these studies have yielded inconsistent results, and our understanding of the central neuronal mechanisms underlying the effect of emotional states on cancer is limited. Moreover, most research in this field has been focused on negative emotional states, such as stress and depression, while the impact of positive mental attributes on cancer biology is largely unknown."  
Don't get me wrong, I believe in "HAPPY"!!!  We all feel better and do better when all is right in our world!  Duh!!!  However, keeping your ass happy when dealing with the reality of a deadly disease, the pain and cost of treatment, the pain and emotional cost to loved ones, the economic and personal value lost due to unemployment when you are too sick to work... I could go on!  Melanoma is NOT easy.  Putting on a happy face, no matter how real (or not) it may be, will not cure your melanoma nor protect you from it!!!  Here's some real data and a bit of a rant:  ASCO 2017: Friends in need are friends indeed! Here's to the caregivers!!!
3.  But, I digress.  In this study, researchers gave real live little ratties either a type of lung cancer or melanoma.  And because we already know that part of our immune system serves us well in fighting cancer (our CD8 t cells and natural killer [NK] cells for instance) while other parts (like the MDSCs) actually SUPPRESS anti-tumor responses and let tumors thrive...the researchers note:  " depleting and adoptively transferring MDSCs, we showed that these cells are both necessary and sufficient to mediate the effects of reward system activation on tumor growth."  In order to test that, very roughly, they made a happy drug ("...we used Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) to specifically control reward system activity...") which they got into these poor little ratties heads {for realz!!!} by attaching it to a cold virus and zapping it into their brains with SRS.  Damn!  It sucks to be a rattie!!!  For the control, they did all the same stuff, just minus the happy pill.  So, according to these researchers, this process allowed the zapped with the happy pill ratties' dopaminergic neurons to get busy with their secretions and stimulations - ultimately impacting the bone marrow, which impacted the MDSC's, making them LESS immunosuppressive.  There.  By the way, the effect was less in the melanoma injected ratties than it was for the lung cancer the researchers actually abandoned the melanoma critters mid-way the study and just used the lung cancer critters.
4.  All in all, this is probably much ado about nothing as it relates to us human melanoma ratties.  EXCEPT!!!  As I said above and in 2014:  "There is talk among melanoma big dogs that combining anti-PD1 with MDSC or T-reg depletion would make it more effective.  I think that holds real promise.  Though...once again...despite my blood and services having been rendered....I have no idea what my MDSC levels were.  Still...I think this could be a real boon to future patients."   So, if this is part of the process to get us there - so be it!!
Now, this...
Sleep-disordered breathing is independently associated with increased aggressiveness of cutaneous melanoma.  A multicentre observational study in 443 patients.  Martinez-Garcia, Campos-Rodriguez, Nagore, et al.  Chest.  2018 Jul 27.

Sleep-disordered breathing (SDB) has been associated with a greater incidence and mortality of cancer, although such findings are inconsistent. However, no large studies are currently available to investigate this association in patients with a specific type of cancer. This study seeks to assess potential relationships between SDB severity and aggressiveness markers of cutaneous melanoma.

443 patients with a diagnosis of melanoma underwent a sleep study within 6 months of diagnosis. General demographics were collected, along with melanoma characteristics and polygraphic parameters consisting of apnea-hypopnea index (AHI) and indices of both continuous and intermittent night-time oxyhemoglobin desaturation (DI4%). Exploration of independent relationships between SDB and various objective melanoma aggressiveness markers (Breslow index, presence of ulceration, presence of regression, mitotic index, stage of severity, damage to the sentinel lymph and spreading of the melanoma) was performed.

Patients in the upper tertiles of AHI or DI4% were 1.94 and 1.93 times more likely, respectively, to present with aggressive melanoma (Breslow index greater than 1mm) than those in the lowest tertiles of these sleep attributes after adjustment for age, gender, tumor location and body mass index. This association was particularly prominent among patients less than 56 years with Breslow index greater than 2 mm. The presence of the additional markers of aggressiveness was also associated with higher AHI and DI4% values.  The severity of the SDB was independently associated with greater aggressiveness of cutaneous melanoma, particularly among younger patients.

1.  Maybe folks who are more worried about their melanoma sleep less well!!!  And sleeping less well about having a potentially deadly disease is completely legit!!!  
2.  Then again, maybe these particular melanoma peeps are less happy about their life and therefore invite melanoma in, like the sad rats in the previous study???  (Y'all know that is NOT what I think!!  Right????)  
3.  Maybe younger folks with melanoma lesions of greater than 2 mm in depth were at greater risk anyway!!!!  Cause that's a thing!!!!  With melanoma: You can never be too rich or too thin! But, you can be too young!!!
4.  Finally, no matter what you think of this report (and I don't think much!!!!) ain't no way insurance is going to pay for sleep studies just because you've been diagnosed with melanoma.  It's hard enough to get them to pay for scans we actually need!!!

Head gett'n itchy yet???  Sometimes we have to think, laugh, yawn, and plain out hope researchers are getting SOMEWHERE that will actually make a difference where we need it!!! Hang tough, ratties!!  c

Tuesday, August 14, 2018

Trial testing MAGE-A3 as adjuvant for Stage III melanoma patients....STOPPED.

If you hadn't heard or were considering MAGE-A3 for your Stage IIIB/C melanoma, there's this: 

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3 positive, stage III melanoma (DERMA):  a double-blind, randomised, placebo-controlled, phase 3 trial.  Dreno, Thompson, Smithers...Kirkwood.  Lancet Oncol.  2018 June 13.

Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting.

DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with, number NCT00796445.

Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group. In the GS-positive population, median disease-free survival was 9·9 months (5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group. Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 for MAGE-A3 vs four for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment.

An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped.

So....disease free survival was no different between the melanoma peeps given a placebo and those treated with MAGE-A3.  To be honest, I don't know how this Phase 3 trial came to be as data I've seen for MAGE-3 has never been very convincing.  But, what do I know? Thanks, Ratties!  Hang tough!  - c

Thursday, August 9, 2018

anti-PD-1 after progression

It is a question many ponder - "Now that I've responded to anti-PD-1, if I recur...what should I do???"  Here is a bit of info toward that answer.....

Outcomes of long-term responders to anti-programmed death 1 and anti-programmed death ligand 1 when being rechallenged with the same anti-programmed death 1 and anti-programmed death ligand 1 at progression.  Bernard-Tessier, Baldine, Martin, et al.  Eur J Cancer. 2018 July 30.

Long-term responders have been observed with anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD(L)1). Optimal duration of therapy in responding and stable disease (SD) patients is unclear with various attitudes encompassing treatment until progression disease, stopping therapy after a defined time frame.
We report the experience of 13 patients who discontinued immune checkpoint inhibitor in phase I trials as per protocol while experiencing a tumour-controlled disease. According to protocols, patients could restart the same immunotherapy if radiological or clinical progression occurred.
Patients were treated for colorectal microsatellite instability-high genotype (n = 5), urothelial carcinoma (n = 3), melanoma (n = 2), non-small-cell lung cancer (n = 2) and triple-negative breast cancer (n = 1) for a median time of 12 months (range 10.6-12). Patients achieved 1 (8%) complete response, 10 (77%) partial response (PR) and 2 (15%) SD. The median progression-free survival 1 (PFS1) defined as the time from the first infusion until progression was 24.4 months (range 15.8-49). The median time free-treatment after discontinuation was 12.6 months (range 4-39.7). Eight patients experienced disease progression and were retreated. Best responses observed after rechallenging were 2 PR (25%) and 6 SD (75%). Median PFS2 defined from the first day of retreatment until disease progression or the last news was 12.9 months (range 5-35.4). No grade 3/4 events occurred during the study period.
Our data suggest that anti-PD(L)1 therapy should be resumed if progression occurs after a planned anti-PD(L)1 interruption. Further prospective studies are needed to confirm these results.
Small numbers here and not all are melanoma patients.  But, some responses on the re-do.  Hang tough, ratties!  Hang tough! - c

Saturday, August 4, 2018

Sew Chaotically! - I scream, you scream for Sewaholic's Hollyburn!!

I've made two Hollyburn skirts already!  Sewaholic made an incredibly workable, flattering, and adaptable skirt with this pattern.  And this one for Roo was SEW much fun in this art gallery cotton, 'I scream, you scream', print!!! 

Not sure my efforts in pattern placment made that much difference, but I'm happy with it!
I used a contoured waistband made as described in the link above.

Isn't she the cutest???  She totally deserves a new back-to-school outfit, even if she is the teacher!!!
And when she's not expanding the craniums of her students with algebra II, pre-cal and calculus, she's off to the races...running in the 5 mile Chattanooga Heroes Run!

So proud of this amazing young woman!  I know you're going to have a great year, Roo!!! - love you, mommy

Friday, August 3, 2018

Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...)

Yes, I've been yelling about this for a while!!  Here are tons of posts/articles:  More than you ever wanted to know on NLR - neutrophil-to-lymphocyte ratio!  In these data sets you will find:

  • Increased baseline NLR was associated with poorer outcomes generally.
  • Multiple studies demonstrate that an NLR less than 5 showed improved progression free survival.
  • A retrospective review showed that increased NLR in high risk, NON-metastatic melanoma patients resulted in poorer outcomes, indicating that Stage III patients might take that measure into account when thinking about how aggressively they should treat their disease.  That result was replicated from a study at Huntsman, where they found that an NLR greater than 2.5 in Stage III patients was a strong predictor of recurrence. 

Now, there's this:

Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. CaponeGiannarelliMallardo, ... Ascierto .  J Immunother Cancer. 2018 Jul 16.

Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors.

This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. ... 
In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR and LDH maintained a significant association with OS in multivariate analysis. Patients with baseline NLR greater than/= to 5 had significantly worse OS and PFS than patients with NLR less than 5, as did patients with baseline dNLR greater than/= to 3 versus less than 3. Optimal cut-off values were greater than/= to 4.7 for NLR and greater than/= to 3.8 for dNLR. Using this greater than/= to 4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR less than 3.8 was also associated with better OS and PFS. 

Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma.

So, the question seems to be, How low can we go???  Cause when it comes to NLR, it looks like the lower the better for our prognosis!!  Still, this is not the whole answer to melanoma care and therapy.  It is one thing to check and speak with your doc about when making the best possible treatment plan for your melanoma.  Hang in there, ratties!!! - c