Leptomeningeal disease - a case study

Intrathecal administration of tumor-infiltrating lymphocytes is well tolerated in a patients with leptomeningeal disease from metastatic melanoma:  A case report.  Glitza, Haymaker, Bernatchez, et al.  Cancer Immunol Res. 2015 Jul 27.

Patients with leptomeningeal disease from melanoma have very poor outcomes and few treatment options.  This is a case of intrathecal administration  [an injection directly into the spinal fluid] of autologous tumor infiltrating lymphocytes (TIL) in a patient with leptomeningeal disease (LMD) which developed after prior treatment with surgery, high-dose bolus IL-2, and systemic TIL infusion and experienced radiographic progression after intrathecal (IT) IL2 therapy.  Pt was given weekly treatment with increasing numbers of IT TIL followed by twice weekly IT IL2.  Analysis of CSF demonstrated increased inflammatory cytokines following the treatments.  Subsequent imaging demonstrated stable disease and neurological deficits also remained stable.  The patient expired 5 months after the initiation of IT TIL therapy with disease progression in the brain, liver, lung and abdominal lymph nodes but, WITHOUT LMD progression.  These results demonstrate safety of IT TIL and support a prospective clinical trial to determine clinical benefit in these patients.

Very sad overall.  Though hopeful in the sense that while IL2 intrathecally didn't help...when combined with TIL it did.  This is a very difficult situation that some melanoma patients and their families face, so any treatment improvements will certainly be a boon.  Why this patient wasn't simultaneously or previously administered an immunotherapy is not mentioned.  But, it seems to me that might have been helpful as well.

Wishing you all my best.  - c

51 years, 51 years...and believe it or not...I'm still here!!!

What a beautiful surprise!  51 years! I am thankful for every one.  Not every  moment was perfect or pain free, but they all combined to build the person I am today.  I like that.  I tried to teach my children and students that while one could learn from perfect examples and textbook cases, there was much to be said for learning from those you didn't wish to emulate, experiences that were less than fun.  I hope I have lived up to my own advice. I am not certain what my future holds.  Is anyone?  I find myself still a bit desperate to "get things done".  There are those who would argue that that was the case for me since birth.  However, I know the change in how I  feel.  Since melanoma.  There is an urgency I can't shake.  And I don't think that's bad.  At first...I wanted to see my children through middle school.  With that accomplished, please....could I just help mentor them through high school?  Set them off to college or the next step they chose?  Once there...might I just help them settle into the lives they have built for themselves?  Not a bit greedy am I?  But, I am.  Greedy for these things and more....  Time with B.  Laughter with friends.  That special light at dusk. A walk in the woods.  The sound of rain.  A beautiful song.  A perfect verse.  A parent helped. The smile of a child.  A diagnostic puzzle solved.  Melanoma thwarted.

And there was my MONTH of BIRTHDAY.  Because I am spoiled ROTTEN!!  A beautiful table built by B.  A picture like a window...into sweet memories and a beautiful river.  A perfectly designed blouse.  Beautifully wrapped and explained sewing toys.  A trip to Moscow...in a cup.  Visits and art from those dear.  And then there was this...from a dear one...who knows me well....

An amazing classical Happy Birthday to YOU!!!

Thanks to all of you.  Celebrate YOUR days....as best you can.  Much love - c

Keeping you informed about the a$$hole: Dr. Dana Hansen from Kent State University

You may remember this post:  Lame lazy phd student 
It was in response to an A$$ HOLE who wanted to interview my peeps about reading the blog of a DYING cancer patient....replete with typo's and crass ass shenanigan's....who was stupid enough to post her shit on MY blog.  I sent her the letter published in the link. Surprisingly (not)...there was no reply.  Funny, Dana.  You liked posting on my blog before!  Well....you know I love my research!!!  Turns out....she's not a student!  She's a chubby weirdo who is actually PAID as an assistant PROFESSOR at Kent State!!!!!!!  Check her out:  http://www.kent.edu/nursing/profile/dana-m-hansen-phd-rn   (Dana, honey!!!  Did you not take diet, nutrition, and exercise classes in your nursing curriculum????)

Anyhow...Miss Dana...DID get my email.  How do I know?  Well, she deleted some of her bullshit...though it is preserved on my original post.  Some of her links in my message have been take down and typo's...at least some of them....have been corrected.  However, this is what I have also learned.....

She posted her crap here:  Blog: My Journey with Inflammatory Breast Cancer

And here:  I have cancer, but it won't have me...  I'm sorry, but does this sound like a dying person to you?

And she went there....here....Dried my tears and threw on my big girl pants  I mean really!!!  Read this post.  Would you post here that you wanted to interview the peep of the "dying" person????  But, a "NURSE" did!!!!!!!!

And this...on a post from 2014:  COPD thread

And here:  carcinoid syndrome flushing You thought THIS chick was dying?????!!!!

And she put this:  on someone's 2014 post!!!

This poor person is freaking out because she SURVIVED!!!!!  Yet Miss Compassionate Nurse Dana posted here too:  Sometimes i feel like i am falling apart

With a sense of humor like this....this lady is NOT on death's door....Don't worry, it's not ebola
Of course PhD Dana couldn't be bothered with figuring that out!!!

And this blogger, while going through some hard times, is training for a triathlon!!!!!  cancer cures life

Sadly...there are more.  However, I feel I have proven my point and wasted enough time.  You are one sick cookie, Miss Dana PhD Hansen.  And to all of us proud to be in the nursing profession...an extreme embarrassment.  Kent State...you pay this person????  Seriously?????  WOW!

(Oh, yea....my peeps.  I'll be forwarding this post to Kent State...and Ms Dana.  Don't you worry!!!)  As if having cancer wasn't enough!!!  - c

Itching and vitiligo associated with progression free survival after Pembro/Keytruda???!

Pembrolizumab cutaneous adverse events and their association with disease progression.  Sanlorenzo, Vujic, Daud, Algazi, et al.  JAMA Dermatol.  2015 Jul 29.

While immunomodulatory anticancer drugs, like anti-PD1 are promising....little is known about cutaneous adverse events caused..and their possible correlation with treatment response.  Single institution, retrospective medical record review, March 1, 2011 - May 28, 2014.  83 patients from 2 clinical trials...who had at least 1 dose of pembro and at least 1 f/u visit.  43 patients had 10mg/kg q 3 wks, 24 had 10mg/kg q 2 wks, and 16 had 2mg/kg q 3 weeks.  66 were melanoma pts, 15 were lung, 1 prostate cancer and another was treated for Merkel cell carcinoma.  

35 patients (42%) developed cutaneous AE's.  Most common = papular eruption (24[29%]), itching (10[12%]), hypopigmentation {vitiligo} (7[8%]).  All 7 pts who developed hypopigmentation were being treated for melanoma.  Survival analyses showed that patients who developed cutaneous AE's had significantly longer progression-free intervals in all 3 treatment dosage groups, compared to patients who did not develop cutaneous AE's.

CONCLUSION:  Pembro was associated with side effects related to the skin in 42% of patients.  The development of these cutaneous AE's, especially hypopigmentation in patients with melanoma, could point toward better treatment response.


Link to post describing general side effects from anti-PD-1 and why we get them:  Side effects of anti-PD1 (Nivo in this case, though data is very similar for Pembro)

Link to post from ASCO 2015:  How Nivo side effects are associated with survival

Link with info from 2015 with article demonstrating positive link between vitiligo and remission of melanoma, back ground info, and white patches:  Vitiligo a good prognostic indicator for melanoma

Pretty much what we've been hearing (and seeing!!) already.  There has got to be something going on between the CD8 T cells, dendritic cells and melanoma, especially since only the melanoma patients in the study developed vitiligo.  B's been screaming about this for years!!!  It is clear that a link between these things exists...but we don't yet know how to ELICIT the vitiligo response so that more melanoma patients GET a response!  Come on researchers!!!  We've got a vaccine for ebola, a reliable treatment for Hep C...let's do this!!!!! - c

For Mat: CDK4/6 inhibitors, PLX8394, or copper chelation?????

Thought about you all day my friend.  Between planting 9 million iris bulbs and repairing a brick wall (mortar mix is an amazing desiccant from which my hands may never recover) at my daughter's "new" house, while shouting curse words (in my head) on your behalf, that even my most tolerant blog audience may find cringe worthy...this is what I (and a brain far better than mine) came up with:

For those unaware of Amazing Mat...I am thinking of a CURE for someone already experienced in BRAF/MEK, ipi, and Keytruda with a brain met near the optic nerve.

Here goes: 

CDK4/6 inhibitors:  
90% of melanoma patients are positive for CDK4/6.
The inhibitor has been proven to cross the blood brain barrier.
Sosman at Vanderbilt has been working with this under the name of LEE011 for some time.
Clinical Trial - NCT01777776: LEE011 and LGX818  is noted to be "active, but not recruiting".
Check out this post from ASCO 2015 (second abstract) where one version (P1446A-05 [voruciclib]) is combined with vermurafenib:  ASCO 2015 new BRAF inhibitor combos
Several other trials with the drug are also noted to be "suspended".  On researching them, the suspension does not appear to be due to patient problems, rather they are due to decisions made by BIG Pharma.
Another CDK4/6 inhibitor:  Palbociclib (PD-0332991) demonstrated "stability" in 27% of patients with melanoma and other cancers.  In another study, a partial response was found in 1 of 31 patients and stability in 29%.
When LEE011 and Binimetinib were combined:  Folks with NRAS mutant melanoma (which may be precluded by your BRAF + status, Mat....but you never know) demonstrated a partial response of 43% as well as stable disease in 43%....per report in Jan 2015.
It's a long shot....but I would call Sosman.  What the heck?  All he can say is no.

A more effective, new generation, BRAF inhibitor - PLX8394?!!!
PLX8394  treats wild and mutated BRAF status melanoma.
May be more effective in BRAF mutated tumors not responsive to other BRAF inhibitors.
Clinical trial #:  NCT02428712 - A study of PLX8394
You have to be refractory to BRAF/MEK, ipi and/or pembro (CHECK!!!).
Do have to have stable brain mets for one month, but sounds pretty flexible and can even be stable on prednisone.
Currently recruiting in Texas, Michigan, Arizona and Utah.

Copper chelation:
Apparently copper is an important co-factor for BRAF mutant melanoma and there is some animal evidence that reducing body levels of copper may inhibit melanoma cells.  Copper chelation for BRAF mutated disease
What's the easiest way to do this?  Duke has been looking at this with an already available drug used to treat copper overload:  Trietine combined with vemurafenib.   Copper starvation could be a promising treatment for some cancers
Clinical trial #:  NCT02068079  Copper chelation and Duke Study
Unfortunately, this study is also "active, but not recruiting".
I would still call.   But, I'm like that.

Much love and warm wishes.  Still thinking. - c

Nivo/Opdivo effective no matter BRAF!!!!

Efficacy and safety of Nivolumab in patients with BRAF V600 Mutant and BRAF Wild-type advanced melanoma:  A pooled analysis of 4 clincal trials.  Larkin, Lao, Urba, Wolchok et al.  JAMA Oncol.  2015 July 1.

The anti-PD1 antibody, nivolumab, has demonstrated clinical activity in patients with advanced melanoma.  The activity of nivo in subgroups of patients with tumors which have wild-type BRAF kinase vs patients with tumors having mutant BRAF has not systematically been explored in a large dataset.  This is an analysis of data pooled from 4 clinical trials of nivo in 440 patents with unresectable stage III of stage IV melanoma who had been tested for BRAF mutational status.  Nivo was given IV at doses of 0.1, 0.3, 1.0, 3.0 or 10.0 mg/kg every 2 weeks until disease progression, discontinuation due to adverse effects, withdrawal, or end of study.  Most patients (83%) were given 3 mg/kg.

Of the 440 patients from 4 clinical trials, 334 were BRAF wild-type and 106 were positive for the BRAF V600 mutation.  In patients evaluable for response, the objective response rates were 34.6% for the 217 patients with wild-type BRAF status and 29.7% for the 74 with mutant BRAF status.  The objective response rates did not seem to be affected by prior BRAF inhibitor therapy, prior ipi therapy, or PD-L1 status of the tumor.  The median duration of objective response was 14.8 months for wild-type BRAF and 11.2 months for mutant BRAF.  Median time to objective response was 2.2 months in both patients groups.  Incidence of adverse events were 68% in the wild-type BRAF group and 58% in the mutant BRAF group.  

The results of this retrospective analysis suggest that nivo has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF, regardless of prior BRAFi or ipi treatment.

1.  Suspect that my trial ratties were reviewed given the dosages.
2.  A little surprised that there were so few mutant BRAF patients as the breakdown is about 50/50 BRAF positive vs BRAF wild-type in melanoma patients.  Wonder if trial requirements played a role.
3.  Still getting conflicting info of whether prior ipi and PD-L1 status affect response rates.  Hope that will clear up soon.
4.  Good info for lots of patients!!!  This was reported at ASCO 2014:  Nivo/opdivo effectiveness in melanoma

Hang in there my friends! - c

A really good review of treatment data for Melanoma Brain Mets!!!

Clinical Management of Multiple Melanoma Brain Metastases:  A Systematic Review
Goyal, Silk, Tian, et al.  JAMA Oncol.  2015 May 21.

Treatment of brain mets from melanoma is controversial and includes surgical resection, SRS, and WBRT.  Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing some subsets of patients to have long-term survival.  Given this, brain met management in melanoma is continually evolving.  A PubMed database search for related terms...published from Jan 1995 - Jan 2015....was reviewed.  Of 2243 articles initially id'd, 110 were selected for full review.  Of these, 73 were included here.  

Level 1 evidence supports use of SRS alone, WBRT, and SRS with WBRT.  Although the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes.  Cytotoxic chemo has largely been ineffective; targeted therapies and immunotherapies have been reported to have high response rates and deserve further attention in larger clinical trials.  Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Emerging data exist to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for WBRT.

A much better review of data regarding the treatment of melanoma brain mets incorporating the new systemic therapies.  And, YES!!!!  We certainly need studies looking at the results of anti-PD1, ipi, and BRAFi when combined with SRS.  These treatments were withheld from folks with brain mets for far too long!  Hopefully that tide has turned!!!

Sad that all this is taking so long given this data out of ASCO 2013!!!  Brain Mets in melanoma the latest from ASCO 2013

Info from ASCO 2015 re: Pembro/Keytruda and an ongoing brain met study:  ASCO 2015 pembrolizumab/keytruda

Also out of ASCO 2015....ongoing study with Nivo/Opdivo and ipi/Yervoy for brain mets:  ASCO 2015 new nivo/ipi trial for melanoma brain mets

Discussion of brain met patients in clinical trials from 2014:  Should melanoma brain met patients be allowed in clinical trials?

More data that ipi and anti-PD1 work in the brain:  Anti-pd1 and ipi and t cells in the brain

Vemurafenib works in the brain:  Vemurafenib really does work on brain mets!

Thanks, ratties!  - c