Wednesday, January 29, 2014

Off beat melanoma miles...

Four miles on Sunday.  Robins. Wind.  Thoughts.  Melanoma.  Forgotten.  Remembered.  Words.  Dreams.  Could I?  Will I?  Gifts from those I love.  A mash-up.  Music.  Listening.  Love is a doing word.  Fearless on my breath.

You try....

Teardrop Madness Muse vs Massive Attack

Love, love is a verb.
Love is a doing word.
Fearless on my breath.
Gentle impulsion, shakes me, makes me lighter, fearless on my breath.
Teardrop on the fire. Fearless on my breath.

Water is my eye, most faithful mirror.
Fearless on my breath.
Teardrop on the fire of a confession, fearless on my breath.
Most faithful mirror, fearless on my breath.
Black flowers blossom, fearless on my breath.

Love, love is a verb.
Love is a doing word.
Fearless on my breath.
Teardrop on the fire. Fearless on my breath.

Thanks Fred-o.  - c

Sunday, January 26, 2014

Red, red wine...boosts radiation effect for melanoma????

A potential role for resveratrol as a radiation sensitizer for melanoma treatment.
Fang, Bradley, Cook, Herrick, Nicholl.  J Surg Res, 2013 Aug.

In this study, radiation in combination with resveratrol (RSV) on radioresistant melanoma lines were evaluated by assessment of proliferation and apoptosis.  The researchers found that the melanoma cells were decreased after the addition of RSV to the radiation treatment.  The data suggest that RSV enhances radiation sensitivity of melanoma cells by inhibiting proliferation and promoting apoptosis.  Resveratrol may have a potential role as a radiation sensitizer for melanoma treatment.

Not sure how they spread the love...grapes, red wine, boring IV administration of some compound...

But, I'm time I have to have radiation, I'll be having a glass of pinot!  Cheers! - c

Wednesday, January 22, 2014

Dabrafenib/Trametinib (BRAF/MEK) Combo approved by FDA

Trametinib (Mekinist) - a MEK inhibitor and Dabrafenib (Tafinalar) - a BRAF inhibitor (Seriously...Who names this crap???  AND....why, oh why, oh why, must medications have forty-leven names???  Everyday I have to explain that Ibuprofen, Advil, and Motrin are exactly the SAME THING!!!!  Sorry...small rant.) were both approved in May of 2013 as individual treatments for metastatic or unresectable melanoma that express the V600E or V600K mutation.

On January 10, 2014 the Food and Drug Administration granted accelerated approval for the combination to be used in patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA approved test. I've mentioned before various trials have demonstrated that the combination of these meds created better responses and fewer side effects than when they were used alone.  Approval of the combination was based on the demonstration of durable objective responses in trials where objective response rates and response durations were 76% and 10.5 months with the combo and only 54% and 5.6 months in the single agent arm.  Squamous cell carcinoma was 7% in the combo arm, but was 19% in the single agent arm. The most common (at least 20% incidence) side effects experienced with the combination were:  fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.  The most frequent complicated adverse events (with at least a 5% incidence) were:  acute renal failure, fever, hemorrhage, and back pain.  So...still pretty messy stuff!  But...better than either med alone.  The recommended dose and schedule for trametinib and dabrafenib in combination is:  trametinib 2mg orally once a day with dabrafenib 150mg orally twice daily, continued until disease progression or unacceptable toxicity occurs.  Both meds should be taken 1-2 hours after eating. The trametinib can be taken at the same time as either dose of dabrafenib.

As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.  Full approval is dependent on the results of an ongoing Phase III study.

So....there you go. - c

Sunday, January 19, 2014

"What is the Optimal Treatment of Advanced Melanoma?"

A Conversation with Mario Sznol, MD
By Caroline Helwick. Sept 15, 2013. ASCO post.

Mutation testing:

"Although we consider immune therapy first in almost all patients, we send a tumor sample for mutation testing....(BRAF, NRAS, cKIT)... If the patient does not have a BRAF V600E mutation, we consider that he or she could have other mutations or alterations in BRAF that are not picked up on the conventional test and that could respond to a BRAF or MEK inhibitor, so we may send tissue for a more sophisticated molecular sequencing.  Patients with the unusual mutations or alterations are a vanishingly small population, but that's what personalized medicine is about..."

Treatment initiation:

"The targeted agents are...lower on our list...while some patients can have durable responses to BRAF inhibitors, so far we don't know if these responses are maintained once you stop the drug, unlike with immunotherapy.  If a BRAF inhibitor is indicated, the best recent data indicate it should be used in combination with the MEK inhibitor...  Even when we start targeted therapy first, our goal is to reach a level of response where we might stop the targeted therapy and start ipilimumab.  We also have the option of going back to targeted therapy if there is no response to the immune therapy.... For ipi, it's important to understand that some patients slowly build an immune antitumor response over 3-6 months, but once they respond they often have durable remissions - they just need time to get there...."

Novel Immunotherapeutic Agents:

"We are very excited about these immunotherapeutic agents, currently nivolumab and lambrolizumab, which block PD-1 but also the antibodies that block PD-L1.  About 30% of patients will respond to these agents by objective criteria, and conservatively, about half of this group may achieve very durable responses.  The median response duration to nivolumab is 2 years - the longest we have seen in advanced melanoma.  Even better responses are observed when we combine nivolumab with ipi. We see overall response rates of 40-50%, with about 30% of patients demonstrating at least an 80% tumor regression. This can occur even in patients with very large tumors that are progressing rapidly.  The responses happen quickly and are very deep."

"With anti-PD1, you can tell your patient that he or she will have a 30% chance of responding, and if a response occurs, there is a 50% chance that it will be durable, with almost no toxicity in most patients; toxicity, however, will be greater when PD-1 blockade is combined with ipi.  It's a no-brainer that we will probably offer some form of PD-1 blockade first, alone, or in combination."

"Perhaps we may change this view when we see long-term data from the dabrafenib/trametinib or other BRAF/MEK targeted agent combinations....I still don't know with 100% certainty if nivolumab/ipi is better than nivolumab alone, or better than lambrolizumab alone, or if one anti-PD1/PD-L1 agent is better than another....  We believe that having these new drugs will make some of the current treatment algorithms obsolete..."

Hmmmm....lots yet to learn, indeed.  Best to you all. - c

Friday, January 17, 2014

Where are you Erin Brockovich?

West Virginia needs you!!!!  The president of the company that polluted the water for more than 300,000 residents, a company that has now declared bankruptcy, is also the owner of a newly established firm that will provide financial backing for the newly bankrupt one?????  Are you freaking kidding?

And yes...there is always a tune.....

Poison in the Well, 10,000 Maniacs, Natalie Merchant

"Tell me, what's gone wrong. I tilt my head there, under the faucet, but when I turn it on -- dry as paper. Call the neighbors. Who's to blame for what's going on? In the dark without a clue I'm just the same as you.
O, they tell us there's poison in the well, that someone's been a bit untidy and there's been a small spill. Not a lot. No, just a drop. There you are mistaken, you know you are. I wonder just how long they knew our well was poisoned but they let us just drink on.
O, they tell us there's poison in the well, that someone's been a bit untidy that there's been a small spill. All that it amounts to is a tear in a salted sea. That someone's been a bit untidy, they'll have it cleaned up in a week. 

But the week is over, now it's growing into years since I was told that I should be calm, there's nothing to fear here. But I drank that water for years, my wife and my children!
Tell me. Where to now? If your fight for a bearable life can be fought and lost in your backyard? O, don't tell us there's poison in the well, that someone's been a bit untidy, that there's been a small spill. And all that it amounts to is a tear in a salted sea. That someone's been a bit untidy, they'll have it cleaned up in a week."

Corporate America...just privatize it!  They'll always do the right thing?  Yes?  - c

Wednesday, January 15, 2014

Ipi and radiation...a good combo for melanoma mets...brain and otherwise!!!

We've been hearing more and more about this!  Here are two new articles...

Ipilimumab and radiation therapy for melanoma brain metastasis. 
Silk, Bassetti, West, Tsien, Lao.  Cancer Med. 2013 December.

Ipilimumab, an antibody that enhances T-cell activation, may augment immunogenicity of tumor cells that are injured by radiation therapy.  We hypothesized that patients with melanoma brain metastasis treated with both ipi and radiotherapy would have improved overall survival, and that the sequence of treatments may affect disease control in the brain.  We analyzed the clinical and radiographic records of melanoma patients with brain mets who were treated with whole brain radiation therapy or stereotactic radiosurgery between 2005 and 2012. ...Several patients were identified, 33 of whom received ipi and 37 who did not.  The patients who received ipi had a...median survival of 18.3 months, compared with 5.3 months for patients who did not received ipi.  Ipi and stereotactic radiosurgery were each significant predictors of improved overall survival.  Four of 10 evaluable patients (40%) who received ipi prior to radiotherapy demonstrated a partial response to radiotherapy, compared with two of 22 evaluable patients (9.1%) who did not received ipi.  Ipi is associated with a significantly reduced risk of death in patients with melanoma brain mets who underwent radiotherapy, and this finding supports the need for mulimodality therapy to optimize patient outcomes.

So...40% of patients with melanoma brain mets who had ipi then radiation showed a partial response.  While only 9% of patients treated only with radiotherapy (no ipi) showed the same response.  The numbers of patients in this review are small and wonky...but this effect is showing up more and more as talking points when the melanoma big dogs are interviewed and in the literature.

Combined ipi and radiotherapy for metastatic melanoma.
Menzel, Abendroth, Kashani-Sabet, Minor. Center for Melanoma Research and Treatment, California Pacific Medical Center, San Francisco. International Journal of Radiation Oncology.  October 2013.

The efficacy and toxicity of ipi when combined with radiotherapy (RT) is unclear, though an abscopal effect has recently been reported in multiple patients receiving ipi and subsequent RT. This is our retrospective experience...
Methods:  Melanoma patients treated with ipi and subsequent RT...NON-cranial lesions were identified.  All patients had CT scans within 1 and 3 months of RT initiation and conclusion respectively....
Results:  Ten patients with median age of 65 years received RT via a linear accelerator of CyberKnife...Median number of lesions irradiated lesions was 1 (range = 1-3).  Patients received ipi (3mg/kg, 3-4 doses every 6 months) for a median of 11.9 months pre-RT.  Eight patients had progressive disease, two had stable disease at RT initiation.  At a median follow-up of 12+ months, median progression free survival and overall survival have not been reached.  At last follow-up, 2 patients had complete responses, 4 had partial responses, 1 had stable disease, and 3 had progressive disease.  All irradiated lesions were controlled.  There was one death related to brain mets.  Among 5 patients evaluated for abscopal effect, 2 had progressive disease out of field, 1 had stable disease out of field, and 2 evidenced abscopal effect, with regression or clearance of non-irradiated lesions.
CONCLUSIONS:  Combined ipi and RT is a treatment option in metastatic melanoma with apparently little additive toxicity when hypofractionated RT is employed.  The abscopal effect is an increasingly common phenomenon in observed patients treated with this regimen.

So....Still small numbers...and still sucky results for many...but better than ipi or radiation alone for others!!!  After getting ipi....8 patients had progressive disease and 2 had stable disease.  BUT...after getting RT, 12+ months out - 2 have had a complete response, 4 have had partial responses, 1 has stable disease, and 3 have progressive disease with one death.  Still better than the 8 with progressive disease after ipi alone!!!  Per my Bentie statistician that is a clinical benefit of 70%!!!!  Then there is the abscopal effect to consider, with, of the 5 patients evaluated for it, 2 demonstrating progressive disease out of the field of radiation, 1 with stable tumors out of the field, and 2 with a positive abscopal effect with tumors regressed or cleared in non-radiated areas!  I think we are still unclear if ipi followed by RT is best...or vice versa...or if it matters at all.  I know there are more studies looking at this ongoing.

Fingers crossed for all of you out there!!! - c

Monday, January 13, 2014

Desperately seeking...Susan? No....

...."Anonymous"....seeking...."Ipi success stories"....on MPIP!!!  Well, it looks like you found some!!! For those of you out there seeking...ipi still has a good deal to offer melanoma patients, despite the hub bub around anti-PD1, PDL1, etc., etc.  Ipi is out there and!  The rest are still in trials and being used as marketing tools (more often than not....check out the Bio Fierce quotes from my November 9, 2013 post)....sadly.  Sure, anti-PD1 is showing somewhat better results with somewhat less side effects.  But...waiting on that to get to market is not worth mets in your lungs, brain, who knows where next.  Ipi has helped more people than anything else in melanoma world so far.  And don't forget....many experts in the field....Weber included...feel that what will probably turn out to be the best treatment for melanoma the man himself puts ipi/anti-PD1 sandwich. So, if ipi doesn't do it for you can always take anti-PD1...either the BMS or Merck product when they do come on the market....later.  But...DON'T. DIE. WAITING!

More good news about ipi...especially when combined with radiation...coming soon.
Much love, S. - c

Saturday, January 11, 2014

Vitiligo and melanoma

Vitiligo, caused by the destruction of melanocytes, cells that give our skin pigment, leaving patients' with white blotches on their skin in their absence, has long been realized to be a positive/hopeful sign when it occurs in patients with melanoma.  On extremely rare occasions it begins spontaneously, at other times it follows treatment with immunologic agents like IL2, ipi and anti-PD1.  However and whenever it occurs, the data shows that those patients have a better prognosis than many of their counterparts, with a rough doubling of 10 year survival in Stage IV patients. (Latest pics of my vitiligo are posted on the March 29, 2013 guess we'll find out what happens to me as we go along!!!)  Additionally, vitiligo can occur in folks with no melanoma or treatments (think MJ here) and in fact, 0.4% of Caucasians in the United States have it.  However, we don't really understand it in either case.  What does seem important, is that if vitiligo indicates that the body is getting rid of melanoma cells, then we do need to know better how to induce it in melanoma patients!

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma.  
Byrne, Zhang, Steinberg, Turk.  Journal Of Immunology, 2014, Jan 8, [Epub, ahead of print]

Vitiligo is a CD8 T cell mediated autoimmune disease that has been shown to promote the longevity of memory T cell responses to melanoma.  However, mechanisms whereby melanocyte/melanoma Ag-specific T cell responses are perpetuated in the context of vitiligo are not well understood. These studies investigate the possible phenomenon of naive T cell priming in hosts with melanoma-initiated, self-perpetuating, autoimmune vitiligo.  Using [a certain kind] of CD8 T cells, we demonstrate that autoimmune melanocyte destruction induces naive T cell proliferation in skin-draining lymph nodes...  These...T cells upregulate expression of CD44, P-selection ligand, and granzyme B.  However, they do not downregulate CD26L, nor do they acquire the ability to produce IFN-y, indicating a lack of functional priming. Accordingly, adult thymectomized [removal of the thymus gland because it has a role in central memory T-cells....poor little ratties!!!] mice exhibit no reduction in the severity or kinetics of depigmentation or long-lived protection against melanoma, indicating that the continual priming of naive T cells is not required for vitiligo or its associated antitumor immunity.  Despite this, depletion of CD4 T cells during the course of vitiligo rescues the priming of....T cells that are capable of producing IFN-y and persisting as memory, suggesting an ongoing and dominant mechanism of suppression by requlatory T cells. This work reveals the complex regulation of self-reactive CD8 T cells in vitiligo and demonstrates the overall poorly immunogenic nature of this autoimmune disease setting.

WHEW!!!!  Feel like I just typed in that pretend language my sisters and I would "talk" in with each other as kids!

What I think this says is:  The CD8 T cells that cause vitiligo, promote response to melanoma.  But, we don't know how. So...the researchers checked a certain type of T cell in mice with no thymus (so the mice couldn't use that part of the process to induce vitiligo) and even so, the active T cells continued to produce vitiligo and protection against melanoma.....and they don't know why!

Anyhow, Mary Jo Turk, one of the authors, is the researcher Brent contacted some time back. We tried to connect her research with Weber (he gave his blessing for her to call) so that perhaps my lab results and cells collected could be analyzed in hopes of finding more answers to the vitiligo conundrum...but it doesn't seem that anything ever came of it.  Perhaps it will someday.  B has emailed her some questions regarding this article and if I've got it all wrong or I learn new nuggets, I'll pass them along.

Meanwhile, ran a couple miles in outright balmy weather with birds chirping as though spring were near.  A huge change from the -2 degrees we had here on the mountain just a few days ago!!!  Stay warm! - c

Monday, January 6, 2014

Happy 2014! The start of my second melanoma decade.....

 I hope that each of you got to have a holiday celebration with those you love.  I wish you the very best in the coming year.  I had the blessing of more special time shared with friends and family.  In fact, while driving back from a visit with my sisters in Alabama, the timing and a chance (???) experience was such, that I had much to think about.

To back up a step, as I recount earlier in my blog, I had my first diagnosed melanoma lesion (a black spot/mole on my back) in 2003. I was working on my masters/NP degree at the University of Alabama in Birmingham at the time. Every time I make that drive now (from here to Birmingham and back), I can NOT believe I did that drive, to and fro, at least twice weekly for two years.  Anyhow, when the "spot" came back positive for melanoma, and a complete surgical resection of the area was required, things were bad enough.  Then, when one of the sentinel nodes was positive as well, and a complete lymphadenectomy of the right axilla was needed, I knew I was in more ways than one.  I couldn't do all that, continue to work in the New Born Nursery, take care of kids aged 10 and 12, plus housework AND take full time NP classes at UAB WITH a 6 hour per day, twice weekly, commute.  AND.....I didn't want to be dead!!!!!

So...what's a girl to do?  Go into action!!  Quit the nursery job.  Schedule the surgery.  Share things as best you can with your children.  Talk to your professors.  Dr. Ivey, Dr. will never realize how grateful I am for your efforts and assistance.  They allowed me to take an 'incomplete' in my classes that semester and worked to bend the will of the University so that I could come back the following semester and take the classes needed for that semester AS WELL AS the ones I had incomplete's that I could finish my degree.  Granted that meant, I took two semesters IN ONE on my return.  That's one version of hell, people.  But...I did it.  And, I am grateful.

But....that still left me with: MELANOMA and I DIDN'T WANT TO BE DEAD!  Hanging....out there....just waiting.  Bentie went into action, seeking information, calling experts across the US.  Sending bits of my tumor to Dr. Starz in Germany.  Should we do interferon like my local oncologist recommended?  Should we do the vaccine trial offered in Nashville?  He found the info.  I listened.  Then, I decided.  No.  To both.  I have no regrets.  I don't think either would have made any impact on anything other than a detrimental one on my health, such that I would have been a year away from returning to school...if ever.

Back in the day, folks, there was nothing else for melanoma, even Stage IV.  NOTHING.  Oh, they offered interferon and various weird, ineffective conventional chemo options, but nothing that worked. (Not that things are much better for Stage III melanoma patients today, sadly.) So, I decided since "nothing" worked and the "something" made you quite ill....NOTHING was better.

But...that doesn't change a mood... a heart.  Then, I happened upon this song.  Given to me by my sister, Carla.  (It is hauntingly beautiful, certainly worth a listen using the link below.)

Silence (Delirium) sung by Sarah McLachlan

Give me, release.  Witness me.  I am outside. Give me peace.

Heaven holds a sense of wonder, and I wanted to believe that I'd get caught up; when the rage in me subsides.

Passion, choked the flower....'til she cries no more.  Possessing all, the beauty. Hungry, still, for more.

In this white wave, I am sinking, in this silence.  In this white wave, in this silence, I believe.

I can't, help this longing.  Comfort me.  I can't, hold it all in.'t...let me.

In this white wave, I am sinking, in this silence.  In this white wave, in this silence, I believe.

I have seen you, in this white wave, you are silent.  You are breathing. In this white wave I am free.

And...there it was.  Everything I was feeling, thinking, crying, demanding.  I sent the lyrics to some I thought would understand.  A few did.  Others didn't.  I guess that's about right. return to the point of this piece.  Driving back from my visit with my sisters, on the same stretch of road where melanoma and these words haunted my thoughts...I heard it...AGAIN.  The ipod was on shuffle...but just the place.....where I KNEW....I had listened to it over and over and over again....BEFORE.  So, I let it carry me back to that place.  To the bleakness.  To the rage.  To the place where there is little that anyone else can do.  But, those who do share the 'white wave of silence' are more precious than life or gold.

I hope that in the past ten years I have been able to turn my rage into something positive...for me....for others. I hope that passion will not choke the flower who does indeed huger still for more.  I hope that I have found a way to balance the white wave such that, if not today...then soon...I WILL be free.  And, were always there.  I saw you.  Underwater.  Beneath the waves.  In the rage and the silence.  WITH ME.  - c